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Zellweger spectrum disordersFrom bench to bedsideKlouwer, F.C.C.

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Citation for published version (APA):Klouwer, F. C. C. (2018). Zellweger spectrum disorders: From bench to bedside.

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1Clinical and biochemical pitfalls in the diagnosis of peroxisomal disorders

Femke C. C. Klouwer1,2*, Irene C. Huffnagel1*, Sacha Ferdinandusse2, Hans R. Waterham2, Ronald J. A. Wanders2, Marc Engelen1, Bwee Tien Poll-The1

* Equal contributors

1 Department of Pediatric Neurology, Emma Children’s Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

2 Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Neuropediatrics (2016) 47(4): 205-20

16 | Chapter 1

Abstract

Peroxisomal disorders are a heterogeneous group of genetic metabolic disorders, caused by a defect in peroxisome biogenesis or a deficiency of a single peroxisomal enzyme. The peroxisomal disorders include the Zellweger spectrum disorders, the rhizomelic chondrodysplasia punctata spectrum disorders, X-linked adrenoleukodystrophy, and multiple single enzyme deficiencies. There are several core phenotypes caused by peroxisomal dysfunction that clinicians can recognize. The diagnosis is suggested by biochemical testing in blood and urine and confirmed by functional assays in cultured skin fibroblasts, followed by mutation analysis. This review describes the phenotype of the main peroxisomal disorders and possible pitfalls in (laboratory) diagnosis to aid clinicians in the recognition of this group of diseases.

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Diagnosis of peroxisomal disorders | 17

Introduction

Peroxisomes are small subcellular organelles, which in humans harbor over 50 different catabolic and anabolic enzyme activities. Peroxisomal enzymes are involved in a variety of metabolic pathways of which some are tissue-specific1. Main pathways include lipid metabolism (e.g. β-oxidation of different fatty acids including very-long-chain fatty acids (VLCFAs) and α-oxidation of phytanic acid), synthesis of bile acids, docosahexaenoic acid (DHA) and plasmalogens1–4.Peroxisomal dysfunction causes various biochemical abnormalities in the cell. Dependent on the defective pathway, the levels of specific peroxisomal biomarkers are either decreased or increased, as summarized in Table 1. If peroxisomal β-oxidation is deficient, biochemical abnormalities include increased levels of (straight-chain) VLCFAs, bile acid intermediates and (branched-chain) pristanic acid (diet-dependent). Similarly, (branched-chain) phytanic acid increases if fatty acid α-oxidation is deficient (diet-dependent), whereas oxalate and glycolate levels increase if glyoxylate detoxification is impaired. Furthermore, L-pipecolic acid rises if the peroxisomal enzyme L-pipecolic acid oxidase is deficient and plasmalogens decrease if ether phospholipid biosynthesis is affected (for review see Wanders et al 20145).

Table 1 Peroxisome functions and their correspondent biochemical abnormalities in case of peroxisomal dysfunction.

Peroxisome function Biomarker Abnormality

β-oxidation of VLCFAs (≥C22) Very-long-chain fatty acids

β-oxidation of methyl-branched chain fatty acids (DHCA, THCA and pristanic acid)

Bile acid intermediates DHCA and THCA Pristanic acid

α-oxidation of fatty acids Phytanic acid

α-methyl branched chain fatty acid racemization

Bile acid intermediates Pristanic acid Phytanic acid

Glyoxylate detoxification Oxalate Glycolate

L-lysine oxidation L-pipecolic acid

Ether phospholipid biosynthesis Plasmalogens

Abbreviations: DHCA, dihydroxycholestanoic acid; THCA, trihydroxycholestanoic acid; VLCFA: very long-chain fatty acid. Note: See Table 4 for more detailed information on the different peroxisomal biomarkers in the different peroxisomal disorders.

Peroxisomal disorders can be classified into two subgroups. The diseases that will be further discussed in this review are summarized in Figure 1. The first group are the peroxisome biogenesis disorders (PBDs) caused by a defect in the assembly of peroxisomes. PBDs are autosomal recessive disorders with an estimated incidence of 1:50.000 newborns6. Within this group, two clinically distinct phenotypes can be identified: the Zellweger spectrum disorders

18 | Chapter 1

(ZSDs) and rhizomelic chondrodysplasia punctata (RCDP), of which type 1 and 5 are classified as PBDs. The clinical spectrum is wide with a large difference in disease severity between individual patients. There is some genotype-phenotype correlation with mutations in one of the 14 different known PEX genes7.

Peroxisomal Disorders

Peroxisome Biogenesis Disorders

Single Peroxisomal Enzyme Deficiencies

Disorder Abbreviation Gene name OMIM no.

Zellweger Spectrum Disorders - Zellweger syndrome - Neonatal adrenoleukodystrophy - Infantile Refsum Disease

ZSDs ZS NALD IRD

PEX genes

214100 202370 266510

Rhizomelic chondrodysplasia punctata type 1

RCDP1 PEX7 215100


RCDP5 PEX5 -


RCDP2 GNPAT 602744


RCDP3 AGPS 600121


RCDP4 FAR1 616107

X-linked adrenoleukodystrophy X-ALD ABCD1 300100

Peroxisomal acyl-CoA oxidase 1 defiency

ACOX1 deficiency

ACOX 264470

D-bifunctional protein deficiency DBP deficiency HSD17B4 261515

Refsum disease (classic) RD (CRD/ARD) PHYH/PEX7 266500

α-methylacyl-CoA racemase deficiency

AMACR deficiency

AMACR 604489

Figure 1 Classification and nomenclature of peroxisomal disorders.

The second group are the peroxisomal disorders caused by a single peroxisomal enzyme deficiency (SED). Biochemical abnormalities and clinical symptoms depend on the specific pathway in which the deficient enzyme is involved. The most common SED is X-linked adrenoleukodystrophy (X-ALD), with an incidence estimated around 1:16.800 newborns8. X-ALD is caused by a defect in the peroxisomal ABC half transporter adrenoleukodystrophy protein (ALDP), due to mutations in the ABCD1 gene9. This impairs peroxisomal β-oxidation of VLCFAs, leading to an accumulation of VLCFAs in these patients10,11. Other SEDs are: Refsum disease (RD), acyl-CoA-oxidase type 1 (ACOX1) deficiency, D-bifunctional protein (DBP) deficiency, α-methylacyl-CoA racemase (AMACR) deficiency, Sterol Carrier Protein X (SCPx)

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deficiency, Peroxisomal Membrane Protein 70 (PMP70) deficiency, RCDP type 2, 3 and 4, bile- acid-CoA-amino acid transferase (BAAT) deficiency, and hyperoxaluria type 112–21.This review focuses on the clinical presentation of the most common peroxisomal disorders with neurological involvement, the diagnostic approach and possible pitfalls during this process. SCPx deficiency, PMP70 deficiency, BAAT deficiency and hyperoxaluria type 1 are beyond the scope of this paper and will not be further discussed. A flowchart with a diagnostic algorithm for peroxisomal disorders will be introduced [Figure 2].

Figure 2 Diagnostic flowchart of peroxisomal disorders.aPlasmalogens measured in erythrocytes, others in plasma. bIn ZSDs, mutation analysis is preceded by complementation analysis. ACOX1, peroxisomal acyl-CoA oxidase type 1; AMACR, α-methylacyl-CoA racemase; DBP, D-bifunctional protein; RCDP, rhizomelic chondrodysplasia punctata; RD, Refsum disease; VLCFAs, very-long-chain fatty acids; X-ALD, X-linked adrenoleukodystrophy; ZSD, Zellweger spectrum disorder.

20 | Chapter 1

Clinical Presentation

Peroxisomal disorders are characterized by a broad range of biochemical abnormalities, as a consequence of the deficiency of peroxisomes or a deficiency of a single peroxisomal enzyme. Furthermore, the clinical spectrum is equally broad, ranging from patients that present in the neonatal period to patients with minor symptoms manifesting in adulthood. Despite this phenotypic variability, there are recognizable patterns in clinical presentation that suggest a peroxisomal disorder. Organ systems that are usually affected are the central- and peripheral nervous system, the eye, the auditory nerve, the liver, the adrenal glands, and the skeletal system. Patients can present with a severe developmental delay or have normal cognition. Neurological examination may reveal signs of a cerebellar syndrome, myelopathy, and peripheral neuropathy. Liver disease is often present, as is adrenal dysfunction. Many patients have retinopathy with poor visual acuity and hearing deficits. The age of onset of symptoms ranges from the neonatal period to adulthood, although the latter is considered rare for most peroxisomal disorders. Table 2 summarizes the core symptoms of peroxisomal disorders and a differential diagnosis.

Clinically, peroxisomal disorders can be divided into four main groups: (1) ZSDs, together with the single enzyme deficiencies ACOX1 deficiency and DBP deficiency; (2) RCDP spectrum disorders, which consists of RCDP types 1 to 5; (3) X-ALD, and (4) remaining single peroxisomal enzyme deficiencies (i.e., RD and AMACR deficiency in this review). For an overview of clinical symptoms per subgroup, see Table 3.

Patients suffering from a ZSD can roughly be divided into three groups based on age of presentation (1) neonatal-infantile presentation, (2) childhood presentation and (3) adolescent-adult presentation, which also includes most phenotypically atypical ZSD patients26. In general, the disease severity is inversely related to the age of onset.

Zellweger Spectrum Disorders

Traditionally, three clinical presentations have been distinguished: Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD) 22, which are now considered as phenotypic variants within a larger disease spectrum known as the Zellweger spectrum disorders (ZSDs). ZSDs are caused by mutations in one of 13 different PEX genes. Mutations in any of these genes can result in a ZSD phenotype, but there is some genotype-phenotype correlation7. The SEDs DBP deficiency and ACOX1 deficiency show a marked clinical overlap with ZSDs to the extent that they cannot be clinically differentiated13,14,23–25.

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Table 2 Differential diagnosis based on clinical clues appearing in peroxisomal disorders.

Clinical clues Differential diagnosis

Neonatal hypotonia Chromosomal abnormalities (Down syndrome, Prader-Willi syndrome)

Congenital infections

Hypoxic ischemic encephalopathy

Cerebral malformations

Other metabolic disorders (acid maltase deficiency, carnitine deficiency, mitochondrial disorders, congenital disorders of glycosylation)

Spinal muscular atrophy

Congenital muscular dystrophies

Congenital myopathies

Hereditary motor and sensory neuropathies

Bilateral pediatric cataract Idiopathic

Congenital infections

Other metabolic disorders (galactosemia)

Lowe syndrome

Developmental regression Encephalitis (infectious, toxins, autoimmune)

Seizure disorders

Brain tumors

Chromosomal disorders

Endocrinological disorders (thyroid)

Adrenal insufficiency Autoimmune adrenalitis

Infectious adrenalitis

Adrenal hemorrhage

Adrenal hypoplasia

Deficient cholesterol metabolism

Familial glucocorticoid deficiency

Chronic spastic paresis (MRI spinal cord normal)

Focal lesions pyramidal tracts (tumor, infarct, hemorrhage)

Neuromuscular (primary lateral sclerosis, amyotrophic lateral sclerosis)

Familial spastic paraplegias

Deficiency

Infectious

Other metabolic disorders (Krabbe disease, metachromatic leukodystrophy, cerebrotendinous xanthomatosis)

Iatrogenic (radiation myelopathy)

Sensorineural hearing loss with retinitis pigmentosa

Usher syndrome type I,II

Mitochondrial disorders

Cockayne syndrome

Alport syndrome

Waardenburg syndrome

Rhizomelic shortening of limbs

Achondroplasia

Hypochondrodysplasia

Atelosteogenesis type 1 and 2

Thanatophoric dysplasia

Kyphomelic dysplasia

Abbreviation: MRI, magnetic resonance imaging.

22 | Chapter 1

Neonatal–Infantile Presentation

ZSD patients with a neonatal-infantile presentation usually show a severe phenotype, which closely resembles the originally described classic Zellweger syndrome and is characterized by multiple congenital defects 27,28. Patients typically present shortly after birth with severe hypotonia and seizures. Hypotonia causes secondary problems like feeding problems with failure to thrive. Typical dysmorphic features (mostly craniofacial) include: high forehead, large anterior fontanel and wide sutures, broad nasal bridge, anteverted nares, epicanthal folds, hypoplastic supraorbital ridges and deformed ear lobes29,30 [Figure 3A]. Other dysmorphic features, like transverse palmar creases, ulnar deviation, feet malformations and patellar prominence, may be present31. Additional frequent clinical features include hepatic dysfunction with cholestasis, coagulopathy and hepatomegaly, renal cortical cysts, retinitis pigmentosa, cataract and sensorineural deafness29. This group represents the most severe phenotype. Patients typically do not reach any developmental milestones and usually die during the first year of life32. Clinicians should be aware that because of the prominent hypotonia and craniofacial dysmorphia in these children, a ZSD patient with a neonatal-infantile presentation is sometimes first suspected of having Down- or Prader-Willi syndrome, which can cause a delay in diagnosis.

A B C Figure 3 Different facial appearances in Zellweger spectrum disorders.

A Photograph of a 6-month-old girl with typical craniofacial dysmorphia. Note the high forehead, epicanthal folds, broad nasal bridge, hypoplastic supraorbital ridges, and low-set ear on the left side (right not shown). B A 5-year-old girl with less pronounced craniofacial dysmorphism. A high forehead is seen, along with anteverted nares and a broad nasal bridge. Note the downwards turned mouth. C Photograph of a 18-year-old woman without evident craniofacial dysmorphism. However, yellow discoloration of the teeth is noticeable. A written informed consent was obtained from patient C and from the parents of patients A and B.

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Table 3 Symptoms related to age.

System Symptoms ZSD

sa

RCD

P

X-A

LD

RD AM

ACR

Neo

nata

l per

iod CNS Hypotonia +

Seizures +

Spastic paresis +

Vision Cataract + +

Glaucoma, retinitis pigmentosa +

Hearing Sensorineural hearing loss +

Musculoskeletal Enlarged fontanel +

Contractures, rhizomelia +

Dysmorphic features + +

Cardiopulmonal Congenital heart defects +

Endocrinological Adrenal insufficiency +b

Gastrointestinal Cholestasis +

Hepatomegaly, jaundice +

Other Coagulopathy + +

Failure to thrive +

Earl

y ch

ildho

od CNS Developmental regression +

Developmental delay + +

Hypotonia +

Intellectual disability + +

Seizures + +

Spastic paresis +

Vision Cataract + +

Glaucoma, retinitis pigmentosa +

Hearing Sensorineural hearing loss +

Musculoskeletal Enlarged fontanel +

Contractures, rhizomelia, growth retardation +

Dysmorphic features + +


Increased rate of infections (pneumonia, otitis) +

Dermatological Ichthyosis +

Endocrinological Adrenal insufficiency +b

Gastrointestinal Diarrhea +

Hepatomegaly, portal hypertension, liver dysfunction +

Other Coagulopathy +

Abbreviations: AMACR, α-methylacyl-CoA racemase deficiency; RCDP, rhizomelic chondrodysplasia punctate; RD, Refsum disease (classic); X-ALD, X-linked adrenoleukodystrophy; ZSD, Zellweger spectrum disorders; ACOX1, peroxisomal acyl-CoA oxidase type 1. a Includes ZSDs, ACOX1 deficiency and D-bifunctional protein deficiency. b Adrenal insufficiency not present in ACOX1 deficiency.

24 | Chapter 1

Table 3 Symptoms related to age. (Continued)

System Symptoms ZSD

sa

RCD

P

X-A

LD

RD AM

ACR

Late

chi

ldho

od CNS Developmental delay + + +

Developmental regression + +

Behavioral changes +

Ataxia + + +

Neuropathy + +

Intellectual disability + +

Seizures + + + +

Spastic paresis + + +

Vision Cataract + + +

Retinitis pigmentosa + +

Glaucoma +

Hearing Sensorineural hearing loss + +

Olfaction Anosmia +

Musculoskeletal Dysmorphic features + +

Osteopenia +




Cardiac conduction abnormalities +

Dermatological Ichthyosis + +

Endocrinological Adrenal insufficiency +b +



Other Coagulopathy +


1


Table 3 Symptoms related to age. (Continued)

System Symptoms ZSD

sa

RCD

P

X-A

LD

RD AM

ACR

Adu

lthoo

d CNS Developmental delay + +

Behavioral changes, cognitive deterioration +

Intermittent encephalopathy +

Ataxia + + +

Neuropathy + + + +

Intellectual disability + + +

Seizures + + +

Spastic paresis + + + +

Vision Cataract + + + +

Retinitis pigmentosa + + +

Glaucoma +

Hearing Sensorineural hearing loss + +

Olfaction Anosmia +

Musculoskeletal Dysmorphic features + +

Osteopenia +

Rhabdomyolysis +




Cardiac conduction abnormalities +

Dermatological Ichthyosis + +

Endocrinological Adrenal insufficiency + +




26 | Chapter 1

Childhood Presentation

Although partial overlap with the neonatal-infantile presentation exists, the disease spectrum of the childhood form is more variable. Onset is usually within the first or second year of life. Children may first come to attention because of delayed developmental milestone achievements or hypotonia. Progressive bilateral visual- and sensorineural hearing impairment is a consistent feature. Ocular abnormalities include retinitis pigmentosa, cataract, optic nerve atrophy, glaucoma and brushfield spots. Liver dysfunction with hepatomegaly and portal hypertension, (partly) vitamin-K dependent coagulopathy, prolonged jaundice and cholestatic liver disease are typical. The facial dysmorphia is usually less pronounced than in patients with a neonatal-infantile presentation [Figure 3B]. The anterior fontanel often closes after the first birthday, although in our experience sometimes not even before 24 months of age. Patients are at risk of developing adrenal insufficiency, epilepsy, osteopenia and renal cysts or calcium oxalate stones (due to the hyperoxaluria). Regression with loss of acquired skills can occur due to progressive leukoencephalopathy. Prognosis is variable, depending on the combination of symptoms, but most patients die in late childhood33. The majority of children with ACOX1 deficiency grossly resemble patients with a childhood presentation of ZSD, with a mean age of regression of 28 months. However, adrenal insufficiency has so far not been described in this disorder23.

Adolescent–Adult Presentation

Because the phenotypical spectrum of this group is much broader and less well established, clinical diagnosis is more difficult. Sensorineural hearing loss and the earlier described ocular abnormalities are important clues, whereas additional symptoms and signs can be absent or occur later in life. At the mildest end of the ZSD spectrum, patients may only have visual- and hearing impairment with non-specific symptoms, like teeth-and nail abnormalities34. Cognitive development can vary from preservation of intellect to severe retardation. Very subtle craniofacial dysmorphic features can be present, but in many other cases they are completely absent [Figure 3C]. Adrenal insufficiency is common, although asymptomatic in more than 50% of the patients35. Slowly progressive leukoencephalopathy may occur, but is usually clinically silent until an advanced disease stage26. Some may develop progressive peripheral neuropathy, cerebellar ataxia and pyramidal tract dysfunction36. Patients initially presenting with cerebellar ataxia, with or without peripheral neuropathy have been reported37–39. All other abnormalities described in the group of patients with a childhood presentation of ZSD can be present to some extent, but are generally much less severe. Prognosis in this group mainly depends on the involved organ systems, but a significant number of patients survives into adulthood. Liver disease can be the cause of death. Although most patients reported with DBP deficiency resemble the neonatal-infantile group40, a few patients with an adult-onset have been identified41.

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In ACOX1 deficiency, two adult siblings have been reported with mainly neurological symptoms and mild cognitive impairment 42. It should be emphasized that although this group of patients is often referred to as mild, most patients are still severely affected with considerable disability.

Rhizomelic Chondrodysplasia Punctata SpectrumDespite the various molecular defects in the different types of RCDP [Figure 1], RCDP type 1, 2, 3 and 5 are in most cases clinically indistinguishable43,44. This is probably because the main biochemical defect they have in common is plasmalogen deficiency. Based on disease severity we can subdivide RCDP type 1, 2, 3 and 5 in a severe and mild phenotype. The phenotype of patients within the RCDP spectrum strongly correlates with plasmalogen levels, with the lowest levels of plasmalogens in erythrocytes in patients with the severe phenotype45–47.Patients with the severe phenotype are generally recognized in the newborn period with typical symmetrical shortening of the proximal extremities (rhizomelia) and typical facial dysmorphia, like a long philtrum, prominent forehead, hypoplastic midface and upturned nasal tip48 [Figure 4B]. Bilateral congenital cataracts are usually noted and congenital cardiac defects are reported in up to 50% of patients with RCDP type 1. These include septal defects, patent ductus arteriosus, hypoplasia of the pulmonary artery, tetralogy of Fallot and mitral valve prolapse49. In early childhood, the severe growth retardation, developmental delay, spastic paresis, seizures, respiratory problems and contractures become apparent. Patients develop only very limited verbal communication, are not able to sit or walk without support and often require tube feeding 45,50,51. If patients with the severe phenotype survive the neonatal period, survival well into childhood or even adulthood is possible in our experience. This is probably due to the improved supportive care over the past decades49. Although the three described patients with RCDP type 4 demonstrated similar profound growth retardation, developmental delay, pyramidal tract dysfunction and seizures, other clinical features differ from the remaining RCDP types. The patients were found to lack the characteristic rhizomelic shortening of the long bones and displayed symptoms of neurological regression and neonatal hypotonia which are atypical for the classic RCDP phenotype17. In patients with the milder phenotype of RCDP there is no, or only minor, shortening of the proximal extremities. Furthermore, growth retardation and developmental delay are less severe 45–47,51 [Figure 4B]. Diagnosis is more challenging due to the aspecific nature of the presenting symptoms. The four very recently reported patients with RCDP type 5 demonstrate a similar mild phenotype44. Patients with the mild phenotype probably have a (near) normal lifespan.

28 | Chapter 1

A B A

Figure 4 Phenotypical appearance in mild and severe RCDP.

A Photograph of a 7-year-old girl with a severe RCDP phenotype. Besides facial dysmorphism (prominent forehead, long philtrum, low-set ears, and thin upper vermillion border), contractures, and evident rhizomelic shortening of the arms and legs are present. B A 1-year-old boy with a mild RCDP phenotype. No evident craniofacial dysmorphism is present, rhizomelic shortening of the arms is very subtle. RCDP, rhizomelic chondrodysplasia punctate. A written informed consent was obtained from the parents of both the patients.

X-linked Adrenoleukodystrophy

The main clinical features of X-ALD are adrenal insufficiency with a progressive myelopathy. Some patients develop progressive cerebral demyelination. X-ALD was historically divided into distinct phenotypes, but it is more accurate to consider it as a progressive disease52. Patients with X-ALD are asymptomatic at birth. Most (about 80%) develop adrenal insufficiency during childhood, but age of onset is highly variable53. When patients are in their third or fourth decade of life, symptoms of a slowly progressive myelopathy occur54. This can be either with or without peripheral neuropathy55. Initial symptoms are urge incontinence and a spastic gait pattern, but eventually severe impairment with wheelchair dependency occurs. Testicular insufficiency can be present, but is often subclinical56.X-ALD patients are at risk to develop a rapid progressive cerebral demyelination with an estimated life time risk of 60%57. Behavioral changes can be the first sign of cerebral demyelination and may initially be attributed to attention deficit hyperactivity disorder in childhood, or psychiatric illness like depression or schizophrenia in adulthood. As the cerebral

1


disease progresses, cognitive dysfunction, spastic paresis, ataxia and epilepsy become evident57,58. In this stage, progression is rapid and patients have a very poor prognosis. They lose ability to walk, speak or understand language over the course of months52. Women with X-ALD develop a chronic, slowly progressive myelopathy. Adrenal insufficiency and cerebral disease are extremely rare in women with X-ALD59. Female patients with X-ALD are sometimes erroneously diagnosed with primary progressive multiple sclerosis or cervical myelopathy. We know a patient who underwent decompressive cervical laminectomy, while the symptoms were caused by chronic myelopathy due to X-ALD. When boys or men present with adrenal insufficiency (especially in the absence of organ-specific antibodies), X-ALD should be considered. Clinicians should consider X-ALD in patients, both male and female, with chronic myelopathy with a normal magnetic resonance imaging (MRI) of the spinal cord. Typical white matter abnormalities in cerebral ALD on brain MRI, are almost pathognomonic for X-ALD and will be discussed below58.

Single Peroxisomal Enzyme Deficiencies: Refsum Disease and AMACR Deficiency

Refsum Disease

RD is both genetically and phenotypically completely distinct from IRD. Patients with RD usually present in late childhood or adulthood. Initial symptoms are usually poor visual acuity due to retinitis pigmentosa, and anosmia. Later in the disease course sensorineural hearing loss, peripheral neuropathy, ataxia, ichthyosis, and cardiac arrhythmias may occur, but not all patients develop the full spectrum of symptoms12. Short metacarpals and metatarsals are found in up to 30% of patients60. Acute exacerbation of symptoms can be precipitated by intercurrent illness because of the release of massive amounts of phytanic acid from adipose tissue in the catabolic state12,61,62. Clinical features of RD can mimic other peroxisomal diseases, some types of spinocerebellar ataxia or α-/β-hydrolase 12 deficiency37,63,64. RD is extremely rare, with only several dozen patients reported in the literature.

Alpha-Methylacyl-CoA Racemase Deficiency

Only 10 patients with AMACR deficiency have been reported and data on clinical presentation is limited. Several patients have been diagnosed with an adult-onset peripheral neuropathy, retinitis pigmentosa, epilepsy and intermittent encephalopathy, but several cases with a neonatal onset of fulminant liver disease presumably due to bile acid abnormalities have been reported 64–72. No data on the natural history of AMACR deficiency is available.

Laboratory Diagnosis of Peroxisomal DisordersClinical suspicion of a peroxisomal disorder requires confirmation and specification of the diagnosis by a combination of biochemical tests in blood, urine, and/or fibroblasts. Although

30 | Chapter 1

the results of these tests are fairly specific, no single laboratory test can rule out a peroxisomal disorder. It is important that different peroxisomal pathways are represented in these tests, because the diagnosis can be missed if only one is studied. In the future, molecular analysis may replace biochemical testing as the first tier test for the diagnosis of peroxisomal disorders as next generation sequencing (NGS) becomes widely available, especially because of the genetic heterogeneity of peroxisomal disorders. However, in our opinion, analysis of peroxisomal metabolite profiles in blood followed by detailed studies in fibroblasts remains an important pillar for the diagnosis of peroxisomal disorders, to characterize the identified defect, to prove pathogenicity of the identified mutations, and in the management of patients.We will now discuss the most important biochemical tests for peroxisomal disorders with an emphasis on diagnostic pitfalls. [Figure 2] shows a flowchart with a diagnostic algorithm for peroxisomal disorders.

Biochemical Analyses and Functional Studies in Fibroblasts

Zellweger Spectrum Disorders, ACOX1, and DBP Deficiencies

Peroxisomes have both catabolic and anabolic functions and peroxisomal dysfunction causes both accumulation as well as deficiencies of intermediary metabolites. Many assays are therefore based on the measurement of metabolite levels in readily accessible materials such as plasma, erythrocytes, and urine. In addition, metabolite levels can also be measured in cultured skin fibroblasts. Other studies which can be performed in fibroblasts include (1) immunofluorescence microscopy analyses to study the presence/absence and morphology of peroxisomes, (2) measurement of overall peroxisomal α- and β-oxidation rate, (3) immunoblot analysis to evaluate protein levels and processing of peroxisomal proteins, (4) single enzyme activity measurements, and (5) complementation analysis to pinpoint the defective PEX gene in case of a ZSD. Available tests in plasma, erythrocytes, and fibroblasts are summarized in [Table 4]. When a ZSD or clinically indistinguishable SED is suspected, the first tier test is usually metabolite analysis in plasma, erythrocytes, and urine, followed by investigations in fibroblasts. The metabolites that can be analyzed in plasma include VLCFAs (including C24:0/C22:0 and C26:0/C22:0 ratios), polyunsaturated fatty acids, bile acid intermediates di- and trihydroxycholestanoic acid (DHCA and THCA), phytanic acid, pristanic acid, and pipecolic acid. In erythrocytes, plasmalogens can be measured. Additionally, abnormalities in urine can be found in patients with a ZSD: the bile acid profile can be abnormal (with detectable DHCA and THCA) and the excretion of pipecolic, glycolic, and oxalic acids may be increased.Fibroblasts analysis is often required to come to a definite diagnosis, because of the overlap in clinical symptoms and metabolite abnormalities for several peroxisomal disorders. It is imported to stress that all the above mentioned biochemical parameters can be normal in ZSD patients, especially in those with mild or atypical phenotypes36. This is also the case in DBP deficiency, where multiple patients without abnormalities in plasma have been identified73–75.

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Plasmalogen biosynthesis is consistently unaffected in DBP deficiency patients24. In ACOX1 deficiency patients, only the levels of VLCFAs are abnormal in plasma, without any of the other above described abnormalities13.

If the test results are normal in plasma and urine, but a high level of suspicion for a ZSD remains, additional testing in fibroblasts should be considered to definitely rule out a peroxisomal disorder. We know of multiple patients with a ZSD or DBP deficiency with normal or only mildly abnormal parameters in plasma, but clear abnormalities in fibroblasts.

Rhizomelic Chondrodysplasia Punctata Spectrum

The most sensitive biomarker for RCDP is the plasmalogen level in erythrocytes76. All RCDP types, both mild and severe, are characterized by a deficiency of plasmalogens. This is not specific for RCDP, however, because patients with a ZSD can also have low levels of plasmalogens. Additionally, in patients with RCDP type 1 and 5 the level of phytanic acid in plasma can be elevated 44,45,47, which may also occur in ZSDs, DPB deficiency, RD and AMACR deficiency. Elevation of phytanic acid in plasma can be the only abnormal biochemical parameter in patients with RCDP type 1 with an RD-like phenotype77. Differentiation between RCDP and RD is possible by fibroblast analysis, after which genetic testing can confirm the diagnosis. Note that phytanic acid levels are highly dependent on diet. Affected newborns will never have increased phytanic acid levels while they are still breast- or formula fed. Patients with near-normal plasmalogen levels in erythrocytes are very rarely reported in RCDP cohorts and most of these patients are diagnosed with RCDP type 145,47,78. Fibroblast analysis can be used to further differentiate between different types of RCDP and can consist of both biochemical analysis and functional assays [Table 4]. Similar to ZSDs, when the diagnosis was made by NGS, biochemical- and radiological work-up for confirmation is still advised.

X-Linked Adrenoleukodystrophy

In males clinically suspected of X-ALD, the diagnosis can be confirmed by measurement of plasma C26:0 levels and the C26/C22 ratio11. False positive results are possible: hemolysis of the plasma sample, a ketogenic diet and non-fasted blood samples (especially in individuals with high peanut (butter) consumption) can cause increased levels of VLCFAs79,80 in individuals without a peroxisomal disorder. Furthermore, elevated VLCFA levels in plasma are not pathognomonic for X-ALD. Other peroxisomal disorders like ZSDs and some other peroxisomal SEDs typically show elevated levels of VLCFA, but are usually easy to distinguish from X-ALD based on clinical features and the fact that in most other peroxisomal disorders additional peroxisomal metabolites are abnormal. Likewise, false negative results for plasma VLCFA testing due to the consumption of rapeseed or mustard seed oil are possible58. Therefore, mutation analysis of the ABCD1 gene is advised in all patients to confirm the diagnosis.

32 | Chapter 1

Tabl

e 4

Bioc

hem

ical

cha

ract

eris

tics

of d

iffer

ent p

erox

isom

al d

isor

ders

and

thei

r lim

itatio

ns fo

r dia

gnos

is.

ZSD

s D

BPA

COX1

RCD

PX-

ALD

RDA

MA

CRRe

mar

ks

Plas

ma

Very

-long

-cha

in fa

tty

acid

sa

b

b

b N

c

NN

Fals

e po

sitiv

es p

ossi

ble

in in

divi

dual

s on

a k

etog

enic

di

et, h

emol

yzed

sam

ples

and

pea

nut r

ich

diet

.

Di-

and

trih

ydro

xy-c

hole

stan

oic

acid

b

N-

NN

NN

In

AM

AC

R de

ficie

ncy

only

the

(R)-i

som

er o

f fre

e- a

nd

taur

ine

conj

ugat

ed D

HC

A a

nd T

HC

A a

ccum

ulat

es.

Phyt

anic

aci

dN

-N

-N

N-

N

N-

Der

ived

from

die

tary

sou

rces

onl

y; d

epen

dent

on

age

and

die

tary

inta

ke. N

orm

al in

new

born

s.

Elev

ated

phy

tani

c ac

id in

RC

DP

only

see

n in

type

1

and

5.

Pris

tani

c ac

idN

-N

-N

NN

N

Der

ived

from

die

tary

sou

rces

onl

y; d

epen

dent

on

age

and

diet

ary

inta

ke. N

orm

al in

new

born

s.

Eryt

hroc

ytes

Plas

mal

ogen

leve

l

-NN

N

bN

NN

Bloo

d sp

ot

C26

:0 ly

soph

osph

atid

ylch

olin

e

N

NN

Fibr

obla

sts

Plas

mal

ogen

syn

thes

is

NN

N

NN

In P

EX7

patie

nts

with

a R

D-p

heno

type

, pla

smal

ogen

sy

nthe

sis

may

be

slig

htly

impa

ired.

DH

APA

T

NN

-N

NN

NN

orm

al in

RC

DP

type

4

Alk

yl D

HA

P sy

ntha

se

NN

-N

NN

NN

orm

al in

RC

DP

type

2 a

nd 4

C26

:0 β

-oxi

datio

n

NN

NN

Pris

tani

c ac

id β

-oxi

datio

n

N

N

N

Acy

l-CoA

oxi

dase

1

-NN

N

NN

N

D-B

ifunc

tiona

l pro

tein

-N

N

NN

NN

Phyt

anic

aci

d α-

oxid

atio

n

NN

-N

N

NIn

RC

DP

only

redu

ced

in ty

pe 1

and

5.

Phyt

anoy

l CoA

hyd

roxy

lase

N

N

N

N

Pero

xiso

mes

N

NN

NN

NPe

roxi

som

al m

osai

cism

can

be

pres

ent i

n ZS

Ds.

In

DBP

- and

ACO

X1 d

efici

ency

abn

orm

al p

erox

isom

al

mor

phol

ogy

may

occ

ur.

1


Abbreviations: ACOX1, peroxisomal acyl-CoA oxidase type 1 deficiency; AMACR, α-methylacyl-CoA racemase deficiency; DBP, D-bifunctional protein deficiency; DHAPAT, dihydroxyacetone-phosphate acyltransferase; RCDP, rhizomelic chondrodysplasia punctata; RD, Refsum disease (classic); X-ALD, X-linked adrenoleukodystrophy; ZSDs, Zellweger spectrum disorders. a Very long-chain fatty acids: C26:0, C24/C22 ratio, C26/C22 ratio. b May be minimally abnormal to normal in exceptional cases. c May be normal in women with X-ALD.

In females suspected of having X-ALD, measurement of plasma VLCFAs may not always be reliable to establish the diagnosis, since 15-20% of women with X-ALD have normal VLCFA levels81. The diagnostic test of choice in women is therefore ABCD1 mutation analysis. Analysis of skin fibroblasts by immunofluorescence microscopy analysis of ALDP can aid to confirm the diagnosis or rule out a peroxisomal disorder in general [Table 4].Newborn screening for X-ALD by measurement of C26:0 lysophosphatidylcholine in dried blood spots is feasible 82. Since this method also identifies patients with a ZSD, ACOX1 deficiency and DBP deficiency, careful clinical evaluation and additional testing should be done to confirm the diagnosis of X-ALD in newborns with a positive screening test. It is important to realize that this screening method will probably not pick up all women with X-ALD. For male patients screening yields potential health benefits as male patients can be offered follow-up to detect the onset of adrenal insufficiency or cerebral demyelination, whereupon treatment can be started. Women with X-ALD usually develop symptoms of myelopathy in adulthood59. There is currently no disease modifying treatment for the progressive myelopathy in either men or women with X-ALD. Therefore, some argue that the criteria for screening as originally formulated in 196883 are not met for X-ALD at this time. Different conclusions will probably be reached in different countries. In New York State (U.S.) screening was implemented. In the Netherlands, newborn screening for X-ALD will be implemented in the near future for boys only.


RD is biochemically characterized by elevated plasma levels of phytanic acid84. As previously stated, accumulation of phytanic acid is dependent on dietary intake. Although phytanic acid levels in RD are usually more than ten times increased, it may reach near-normal levels in patients who are on a diet low in phytanic acid85. Elevated levels of phytanic acid are not specific for Refsum disease. However, other peroxisomal disorders are less likely when other peroxisomal metabolites like plasmalogens, VLCFAs and the peroxisomal bile acid intermediates DHCA and THCA are all normal. Diagnosis can be confirmed by mutation analysis of PHYH and PEX7, either with or without functional assays in skin fibroblasts [Table 4]. In patients with a PEX7 defect and an RD-phenotype, plasmalogen biosynthesis in fibroblasts can be slightly impaired77. These patients are classified as RD patients based on their clinical symptoms, but genetically they should be classified in the RCDP spectrum.Biochemical abnormalities in AMACR deficiency consist of elevated levels of peroxisomal

34 | Chapter 1

bile acid intermediates and the branched-chain fatty acids pristanic acid and phytanic acid64. Pristanic acid β-oxidation is impaired in AMACR deficiency and as a consequence also its precursor phytanic acid accumulates. AMACR deficiency can be differentiated from other peroxisomal disorders with accumulation of bile acid intermediates by measuring isomers of free- and taurine conjugated DHCA and THCA in plasma. In AMACR only the (R)-isomer of free- and taurine conjugated DHCA and THCA accumulates, whereas in ZSDs and DBP deficiency both (S)- and (R)-isomers accumulate86. The finding of an isolated deficiency of pristanic β-oxidation in skin fibroblasts helps to further differentiate between other peroxisomal disorders [Table 4]. Mutation analysis of the AMACR gene is advised to confirm the diagnosis.

Radiological Features of Peroxisomal DisordersZellweger Spectrum Disorders, ACOX1, and DBP Deficiencies

A Abnormalities on brain MRI are common findings in peroxisomal disorders: both developmental abnormalities (like cortical dysplasia, perisylvian polymicrogyria, delayed myelination and germinolytic cysts) as well as later onset progressive lesions (decrease in white matter volume and bilateral ventricular dilatation and white matter lesions) are observed26. In DBP deficiency, white matter atrophy is most pronounced in the cerebellar region24. Rapid progressive white matter lesions can occur in infants with a ZSD and typically originate in the hilus of the dentate nucleus and superior cerebellar peduncles, then progressing to the cerebellar white matter, brainstem tracts, parieto-occipital white matter, splenium of the corpus callosum and eventually all cerebral white matter is diffusely affected87. A small subgroup of patients develops a relatively late-onset rapid progressive white matter disease, but no patients with an onset after the age of five have been reported so far88. In patients with a mild phenotype, slowly progressive and in some cases clinically silent white matter lesions can occur, although the distribution of the white matter involvement is grossly similar89. A subgroup of ZSD- and ACOX1 deficiency patients have no MRI abnormalities at diagnosis89,90. These patients can still develop white matter lesions later in life. Calcific stippling in the epiphyseal- and periarticular regions of long bones can be seen on X-ray in severely affected patients, usually in the neonatal-infantile onset group.


The majority of RCDP patients have characteristic skeletal abnormalities consisting of symmetrical shortening of the proximal extremities (rhizomelia), coronal clefts in the vertebrae and cervical stenosis50,91. The rhizomelic shortening of limbs can be either mild or profound and is usually most evident in the humeri. Punctate calcifications in meta-and epiphyses of long bones can be present in early childhood. X-ray evaluation is advised to diagnose or exclude above described abnormalities in patients suspected of having RCDP. Patients on the severe end of the RCDP spectrum can also have abnormalities on brain MRI, albeit aspecific. These

1


include ventricular enlargement, delay in myelination and progressive cerebellar atrophy. In the mild phenotype, MRI of the brain is often normal46.


MRI of the brain is normal, unless cerebral ALD develops. Cerebral ALD is characterized by rapidly progressive inflammatory demyelinating white matter lesions that show enhancement after administration of gadolinium58,92. Initial lesions are usually in the splenium of the corpus callosum and parieto-occipital white matter (about 80%), but onset in the frontal white matter can also occur (about 20%). Unusual asymmetric lesions have also been reported93,94. The disease is rapidly progressive and in the course of months to a year lesions will extend into other white matter structures93,95,96. MRI of the spinal cord in patients with symptoms due to chronic progressive myelopathy is normal, but may show atrophy and abnormalities on diffusion tensor-based- and magnetization transfer imaging in an advanced stage.

Single Peroxisomal Enzyme Deficiencies: RD and AMACR Deficiency

Hyperintense lesions on T2-weighted brain MRI images have been described in case reports on AMACR deficiency. These lesions are primary localized in the cerebral cortex and the white matter of the pons, basal ganglia, thalami, occipital lobe and cerebral peduncles65,66,68,97. Brain MRI abnormalities in patients with Refsum disease have been described26,98, but no clear pattern can be distinguished and it is not clear if the described MRI changes are solely related to Refsum disease.

Management and Follow-UpZellweger Spectrum Disorders, ACOX1, and DBP Deficiencies

Treatment options in these patients are limited. Interventions are mainly supportive and targeted to abnormal peroxisomal biochemistry, like replacement of deficiencies. Follow-up should be aimed at screening for treatable complications: deficiencies of fat soluble vitamins like A, D and E, coagulopathy (often partly due to vitamin K deficiency), feeding difficulties, dental abnormalities, osteoporosis and hearing- and vision impairment. Regular assessment of liver function, neurological function and cognitive- and motor development is recommended. In ZSDs, periodic screening for adrenal insufficiency, kidney stones and hyperoxaluria is necessary. There is no evidence at this point that these patients benefit from dietary restriction of phytanic acid.


Similar to ZSDs, treatment options for patients who belong to the RCDP spectrum are mainly supportive and include antiepileptic medication in case of seizures, treatment of cataracts,

36 | Chapter 1

and physical therapy to prevent contractures99. Regular assessment of nutritional status and possible cardiac- and orthopedic abnormalities should be performed. No evidence exists at this point that dietary restriction of phytanic acid stops or delays progression of the disease in RCDP patients.


Allogeneic hematopoietic stem cell transplantation (HSCT) in X-ALD patients can arrest cerebral ALD100. However, the therapeutic window is small with an inverse correlation between the severity of clinical symptoms, including radiographic abnormalities, and outcome of HSCT101. Follow-up should therefore be frequent and aimed at early detection of cerebral demyelination, preferably in the phase that patients show no or minor neurological symptoms. This can be done by performing frequent MRIs of the brain with intravenous gadolinium administration. Furthermore, adrenal function should be evaluated regularly during follow-up and if necessary supplementation with hydrocortisone must be initiated58. Treatment and follow-up of symptoms due to progressive myelopathy is solely supportive and includes interventions to reduce spasticity and pain, together with an extensive rehabilitation program.


Treatment of RD consists of either dietary restriction of phytanic acid or elimination of accumulated phytanic acid by plasmapheresis. Avoidance of swift weight reduction and lengthened periods of fasting is recommended to prevent phytanic acid mobilization from adipose tissue12,85. Management of AMACR deficiency is currently only supportive and dependent on the occurring symptoms. Vitamin supplementation is indicated if vitamin deficiencies exist and should be regularly screened for. Since pristanic acid levels in AMACR deficiency patients can reach levels up to 100-fold higher than control levels, we hypothesize that these patients may benefit from a phytanic acid low diet similar to RD patients. Hence, phytanic acid is converted into pristanic acid via α-oxidation. We therefore recommend to consider a phytanic acid low diet in these patients, even though the beneficial effect on clinical outcome is not yet demonstrated in AMACR deficiency.

Genetic Counseling and Prenatal DiagnosisWhen indicated, affected individuals and parents of a child affected by a peroxisomal disorder should be counseled on prenatal and preimplantation genetic diagnosis. In the sex-dependent disease X-ALD, noninvasive fetal sexing can be done in maternal plasma102. Invasive prenatal diagnosis on a chorionic villus or amniotic fluid sample is possible in all peroxisomal diseases, when the underlying mutation has been identified in the index patient. When the specific mutation has not been identified yet, or when no or only one heterozygous mutation can

1


be detected, prenatal testing can be performed using biochemical methods1. In this case, biochemical testing in fibroblasts of the index patient is required. Biochemical prenatal testing can be problematic when the index patient has only minor biochemical abnormalities2.

Conclusions

Peroxisomal disorders are often difficult to diagnose due to their rarity and clinical- and genetic heterogeneity. The recognition of specific clinical clues such as profound neonatal hypotonia, bilateral cataract, developmental regression, adrenal insufficiency, and the combination of retinitis pigmentosa with sensorineural hearing loss are clues for the diagnosis. Recently reported mild and atypical phenotypes make the identification of these variable disease manifestations even more complicated. Biochemical profiles may be normal in plasma or fibroblasts of mild cases and awareness of false-positive- or false-negative results is obligatory. A structured algorithm of performing and interpretation of laboratory testing can help to establish the diagnosis, to prevent misdiagnosis, and to limit the diagnostic delay. Therapeutic interventions are mostly supportive and targeted toward abnormal peroxisomal biochemistry by dietary restriction or supplementation of deficiencies. When the diagnosis of a specific peroxisomal disorder is established, a multidisciplinary team should be assembled for management and follow-up.

Acknowledgments

This work was supported by a grant from ‘Metakids’, ‘Hersenstichting’, and ‘ZonMw’, The Netherlands. We would like to thank the parents of the patients displayed in this review for providing photographs and the permission for publication.

38 | Chapter 1

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