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Pediatric Neurology 48 (2013) 363e366

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Pediatric Neurology

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Original Article

Type III Spinal Muscular Atrophy Mimicking Muscular Dystrophies

Abdulaziz S. Alsaman MD *, Nahla M. AlShaikh MDPediatric Neurology Department, National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia

article information

Article history:Received 16 April 2012Accepted 31 December 2012

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* Communications should be addressed toNeurology Department; National NeuroscienMedical City; P.O. Box 59046, Riyadh 11525, S

E-mail address: aalsaman@kfmc.med.sa

0887-8994/$ - see front matter � 2013 Published byhttp://dx.doi.org/10.1016/j.pediatrneurol.2012.12.027

bstract

ypes III and IV spinal muscular atrophy represent a diagnostic challenge due to the greatariability in their presentation. We report a series of eight patients with type III spinal

muscular atrophy who were followed for a long time for possible muscular dystrophy ormyopathy, confirming its clinical heterogeneity and propensity to delayed diagnosis. Clinicalexamination revealed heterogeneous findings, where the diagnosis of type III spinalmuscular atrophy was not immediately apparent in many patients as their clinical andlaboratory abnormalities were consistent with muscular dystrophy or myopathy. Thepresence of dystrophic features such as hypertrophy of the calves, weakness of the limbgirdle, high serum creatine kinase levels, and myopathic histopathology should not divertattention from the possibility of spinal muscular atrophy. It is strongly recommended to givevariable presentations enough thought and to consider the autosomal recessive type IIIspinal muscular atrophy in the diagnostic evaluation.

� 2013 Published by Elsevier Inc.

Introduction

Spinal muscular atrophy (SMA) is a term applied toa spectrum of autosomal recessive, autosomal dominant, orX-linked recessive heterogeneous groups of neuromusculardisorders with progressive degeneration of the anteriorhorn cells. The autosomal recessive SMA is the mostcommon form and is linked to the 5q11.2-13.3 locus telo-meric survival motor neuron (SMN1) gene mutation.

This form of SMA leads to symmetrical muscular weak-ness, with a tendency to affect the lower limbs more thanthe upper limbs, proximal more than distal, with selectiveinvolvement of axial and intercostal muscles in the mostsevere phenotype but with little effect on face and dia-phragm muscles [1].

Because of the high variability in SMA severity, theInternational SMA Consortium standardized the classifica-tion of SMA, based on age of onset and achieved motorabilities, to four clinical groups (types) [2,3].

Type III SMA (juvenile SMA, Kugelberg-Welanderdisease)patients are able to sit and walk, and their lifespan is not

: Dr. Alsaman; Pediatricce Institute; King Fahadaudi Arabia.

Elsevier Inc.

reduced. SMA III patients usually manifest proximal weak-ness, with the pelvic girdle being more affected than theshoulder girdle. Most of them have exaggerated lumbarlordosis but significant scoliosis and contractures are rare.Gowers’ sign may be present when arising from thefloor. Fasciculation of the tongue is noted and is morecommon later in the course of the disease. Deep tendonreflexes are diminished and often become absent overtime [2,3].

It has been established that the autosomal recessive SMAis caused by mutations in the telomeric copy of the SMN1gene 5q11.2-13.3. A homozygous absence of SMN1 telomericgene exon 7 and 8 or exon 7 accounts for about 95% of typesI, II, and III SMA patients and the remaining 5% of affectedcases are due to compound heterozygous SMN1 exon 7deletion on one and a small intragenic mutation on theother chromosome 5 [4-6].

Based on this relatively uniform mutational spectrumfound in SMA patients, fast, highly reliable, and relativelyinexpensive molecular genetic polymerase chain reac-tionebased testing is available [7].

The estimated incidence of SMA worldwide is 1:6000-10,000, with a carrier rate of 1:40-80 [8,9]. However, weexpect a higher prevalence and carrier rates of SMA casesin communities where consanguineous marriage iscommon [10].

A.S. Alsaman, N.M. AlShaikh / Pediatric Neurology 48 (2013) 363e366364

In Saudi Arabia, from which this case series is reported,studies have shown that the overall consanguinity rateamong Saudi families is 57.7% [11], and the SMA carrier ratewas 1 per 20 persons compared to 1 per 50-80 persons inother parts of the world [12].

This study emphasized the importance of giving SMA IIIreasonable thought in the diagnostic evaluation of patientswith similar clinical presentation, especially in communi-ties where consanguineous marriage is common, sparingpatients and their families invasive investigations anddelayed diagnoses.

Materials and Methods

The clinical data in Table 1 illustrate a series of eight patients whowere referred to a neuromuscular clinic for possible muscular dystrophyor myopathy. These patients were seen between 2008 and 2010, duringwhich they were all diagnosed to have SMA III based on the SMA clas-sification [2,3]. They were selected from a larger group of SMA patientsbecause they came with an initial diagnosis of muscular dystrophy.

Case descriptions

Characteristically, these eight patients had a slowlyprogressive course, with onset of symptoms ranging from 3to 25 years. Their illnesses manifested initially witha clumsy gait and frequent falls while running, then whilewalking, difficulty in climbing stairs, and getting up froma sitting position. Six of the eight patients maintainedindependent ambulation, while the other two patients wereverymuch disabled andwere wheelchair bound by the agesof 16 to 24 years. All but one patient was the product ofa first-degree consanguineous marriage.

Clinical examination revealed heterogeneous findings.Muscle bulk was reduced in all eight patients, but signifi-cant hypertrophy of the calves was noted in three patients.Tongue fasciculation was noted in two patients and lowerlimbs fasciculation in one. Tone was normal in threepatients and decreased in others. The Medical ResearchCouncil scale showed different power scores ranging from 1to 5 to 5 to 5, with lower scores in the proximal than thedistal muscles. Deep tendon reflexes were normal in onepatient but diminished in others. Five patients exhibitedmild to moderate spinal scoliosis and kyphoscoliosis.

These patients underwent many investigations touncover the underlying etiology of their weakness. Musclebiopsy with nonspecific myopathic features and no featuressuggestive of SMA was done in the referring hospital forPatients 1, 5, and 7. It was repeated for three times atdifferent ages and from different sites for Patient 7.

Four patients had their nerve conduction and electro-myography studies done in their referring hospitals, andvariable findings ranging from normal to mild neurogenicor myopathic changes in two patients were reported.Patient 7’s nerve conduction study was done at the insti-tution of this study. The findings were clearly consistentwith peripheral motor axonal neuropathy.

There was a wide range of serum creatine kinase levelsfrom normal levels (21-215 U/L) to a significantly, steadily,higher level exceeding 1000 U/L in three patients.

Electrocardiogram (ECG) in four patients showedtremor-like patterns disrupting the isoelectric line betweenthe normally perceived ECG waves.

The diagnosis of SMA was suspected upon their initialassessment in the institution for this study and confirmedby telomeric SMN1 gene testing where deletions of exon 7were detected in all patients.

Discussion

This series of eight patients exhibits uniformity ofnormal developmental milestones until early juvenile orearly teens years when they start to have slowly progressiveproximal weakness predominantly involving thelimbegirdle muscles. On the other hand, the diagnosis ofSMA III was not immediately apparent in many of them astheir clinical and laboratory abnormalities were more inkeeping with a muscular dystrophy or myopathy.

Such phenotypic heterogeneity of SMA III has beendescribed in the literature. As early as 1955, SMA III caseswere described as a mild variant of Werdning-Hoffmanndisease in a series of patients from three families clinicallyresembling muscular dystrophy with an entirely neuro-genic nature [13].

One year later, in 1956, Kugelberg and Welander [14]described a series of 12 patients with presentationssimilar to limbegirdle muscular dystrophy, but proven tohave neurogenic changes on nerve conduction or electro-myography and muscle biopsy.

The underlying genetic basis may explain, to someextent, the phenotypic heterogeneity in SMA as there aremany disease modifying genes, the most important ofwhich is the SMN2 gene copies because the amount of SMNprotein expressed in tissues appears to be inversely corre-lated with clinical severity [15,16].

The hypertrophy of the calves and the significantly highserum creatine kinase levels seen in many of the patientshave been described in the literature.

It has been reported that although muscle denervation isthe most prominent feature in human SMA, about onefourth of SMA III patients exhibit hypertrophy of the calves,dystrophic phenotype with “myopathic” histopathology,and high serum creatine kinase levels [17-19].

Another finding that suggests the diagnosis of SMAdiagnosis is the tremor-like pattern disrupting the ECGisoelectric line that was noted in four of the patients. SuchECG findings reflect the unseen, but expected, chestmuscles fasciculation due to chest muscles denervation orthe reinnervation process secondary to ongoing degenera-tion of alpha motor neurons [20-22].

The presence of dystrophic features such as calf hyper-trophy, limbegirdle muscle weakness, elevated serumcreatine kinase levels, and myopathic or dystrophic histo-pathology should not totally divert attention from thepossibility of spinal muscular atrophy. For this reason and tosafeguard the patient frommany unnecessary and, at times,invasive and relatively expensive investigations, it isstrongly recommend to give such variable presentationsenough thought and consideration for autosomal recessiveSMA III in the diagnostic evaluation because SMA III isa common disorder worldwide and more common incertain communities with a high rate of consanguineousmarriage and can be easily confirmed in approximately 95%of affected patients by a fast and highly reliable molecular

Table 1. Clinical summary of patients in this study

Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8

HistoryAge 15 years 13 years 29 years 9 years 15 years 12 years 34 years 21 yearsGender Male Female Male Female Male Female Male MaleAge of onset 4 years 3 years 25 years 3 years 4 years 3 years 6 years 11 yearsSymptoms Slowly progressive course, initially with clumsy gait with frequent falls, proximal weakness that involve initially LL then

progresses to involve ULCurrent status Ambulant Ambulant Nonambulant Ambulant Ambulant Ambulant Nonambulant AmbulantConsanguinity First-degree

cousinFirst-degreecousin

First-degreecousin

First-degreecousin

First-degreecousin

First-degreecousin

Unrelated First-degreecousin

Motor ExaminationFasciculation Absent Absent Absent Absent Present Present Absent PresentTone Normal Normal Reduced Normal Reduced Reduced Reduced ReducedPowerULProximal 4/5 5/5 3/5 5/5 4/5 4/5 2/5 3/5Distal 4/5 5/5 4/5 5/5 5/5 4/5 3/5 4/5

LLProximal 4/5 4/5 3/5 4/5 4/5 4/5 1/5 4/5Distal 4/5 5/5 4/5 5/5 5/5 4/5 2/5 4/5

ReflexesUL 1þ 2þ 1þ 2þ 1þ 0 1þ 1þLL 0 2þ 1þ 1þ 0 0 1þ 0

OthersBack [ Lordosis [ Lordosis Normal Normal Normal [ Lordosis [ Lordosis [ LordosisGowers’ sign þve �ve NA þve þve �ve NA þveReferral

diagnosisMusculardystrophy

Myopathy Myopathy Musculardystrophy

Musculardystrophy

Myopathy Musculardystrophy

Musculardystrophy

InvestigationsSerum CK

(21-215 U/L)1937 10 1325 227 780 105 11 1280

NC and EMG Myopathy Normal Normal Not done Not done Not done Motor Axonalneuropathy

Normal

Muscle biopsy Nonspecificchanges

Not done Not done Not done Nonspecificchanges

Not done Nonspecificchanges

Not done

ECHO Not done Not done Not done Not done Normal Not done Normal NormalECG Not done Isoelectric line

tremorNot done Not done Isoelectric line

tremorIsoelectric linetremor

Isoelectric linetremor

Not done

DMD gene Not done Not done Not done Not done No deletion orduplication

Not done Not done No deletion orduplication

Abbreviations:�ve ¼ Negativeþve ¼ PositiveCK ¼ Creatine kinase (reference range in parentheses)DMD ¼ Duchenne muscular dystrophyECG ¼ ElectrocardiogramECHO ¼ EchocardiographyEMG ¼ ElectromyographyLL ¼ Lower limbsNA ¼ Not applicableNC ¼ Nerve conductionUL ¼ Upper limbs

A.S. Alsaman, N.M. AlShaikh / Pediatric Neurology 48 (2013) 363e366 365

genetic polymerase chain reactionebased testing for 5qtelomeric SMN1 mutation.

The authors thank Dr. Jaffar Ali, senior editor and clinical research coordinator atKing Fahad Medical CityeRiyadh, for his helpful input, revision, and editing, of themanuscript.

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