Brief Clinical Report

First African-American Child With JuvenileNeuronal Ceroid Lipofuscinosis

˙Cigdem Inan,1* David Wong,2 Krystina E. Wisniewski,1,3 Arthur L. Rose,1 and Maria A. Musarella2

1Department of Neurology, Division of Pediatric Neurology, State University of New York, Health Science Center atBrooklyn, Brooklyn, New York

2Department of Ophthalmology, Long Island College Hospital, Brooklyn, New York3Department of Pathological Neurobiology, Institute for Basic Research in Developmental Disabilities,Staten Island, New York

The neuronal ceroid lipofuscinoses areamong the most common forms of progres-sive neurodegenerative disease of child-hood. They appear to be panethnic, butthere is a special predilection of the infan-tile subtype in Finland. In the United States,the Batten disease registry of 731 casesshows that juvenile neuronal ceroid lipofus-cinosis (JNCL) is the most common form.Here, we report on the first known African-American child with JNCL. Genetic studyshowed the 1.02-kb deletion typically seenin JNCL cases. Am. J. Med. Genet. 79:335–336, 1998. © 1998 Wiley-Liss, Inc.

KEY WORDS: juvenile neuronal ceroid li-pofuscinosis

INTRODUCTION

The neuronal ceroid lipofuscinoses (NCLs; Battendisease) comprise a group of genetic neurodegenerativedisorders of children and adults. It is the most commonprogressive and fatal neurodegenerative disease inchildhood [Goebel, 1995].

The disorder presents initially with deterioration ofvision, changes in personality, a decline in scholasticperformance, and seizures. Five distinct forms of NCLare recognizable, based on age of onset and naturalhistory. These are classified as infantile, late infantile(LINCL), juvenile (JNCL), adult, and Finnish variant[Dyken and Wisniewski, 1995]. Although the world-wide incidence of NCLs has been reported to be 1.2 in100,000 live births, the incidence of the disease ap-pears to vary among different countries. JNCL andLINCL are the most common forms of NCL in theUnited States and Europe [Goebel, 1995]. Here, we re-

port on the first known African-American child withJCNL, who developed impaired visual acuity startingat the age of 5 years, followed by seizures at 10 yearsand subsequent cognitive decline.

CLINICAL REPORT

A 91⁄2-year-old African-American boy was the firstoffspring of nonconsanguineous parents. His halfbrothers and mother are healthy. There was no familyhistory of seizures or visual problems. The patient wasreported to have had normal growth and developmentuntil age 5 years, when he was noted to have progres-sive visual problems beginning with the left eye andwithin a year involving the right eye. An ophthalmo-logic examination at age 7 years at a medical center inVirginia had confirmed his visual impairment to be ofretinal origin. At age 9 years, he moved to New Yorkand presented to the Kings County Hospital Ophthal-mology Clinic for eye care. Ophthalmologic examinationshowed that visual acuity was light perception with noprojection in both eyes. Extraocular muscles were in-tact with rotatory nystagmus present on all fields ofgaze. Saccades were intact, and pursuits were difficultto evaluate because of his poor vision. A 30 prism di-opter left esotropia was measured. The pupils were re-active without an afferent pupillary defect. Slit lampfindings were normal. Fundus examination showed bi-lateral optic disk atrophy, marked granularity of theretinal pigment epithelium with some bone spicules inthe periphery, poor macular reflex, and severe attenu-ation of arterioles. No ‘‘bull’s eye’’ maculopathy wasevident. Electroretinographic findings were consistentwith rod and cone dysfunction. At this point, he had ageneralized tonic clonic seizure and was admitted.Physical findings including height, weight, and headcircumference were normal. He was alert, oriented,and cooperative. Neuropsychological evaluation wasperformed by using only the verbal subtests of WISC-III. His scores were all below average. On the Kauf-mann test of educational achievement, Woodcock-Johnson educational battery test, and Spache diagnos-tic reading test, he was 3 years below the expectedlevel. He was unable to walk without assistance be-

*Correspondence to: C. Inan, M.D., Division of Pediatric Neu-rology, SUNY Health Science Center at Brooklyn, 450 ClarksonAvenue, Box 118, Brooklyn, NY 11203.

Received 14 October 1997; Accepted 5 May 1998

American Journal of Medical Genetics 79:335–336 (1998)

© 1998 Wiley-Liss, Inc.

cause of impaired vision. Cranial nerve function wasintact except for impaired visual acuity and optic atro-phy. Muscle strength and tone were normal. Deep ten-don reflexes were diminished but present bilaterally.Plantar responses were flexor. Sensory examinationand coordination were normal.

Head computed tomography and brain magneticresonance studies also were normal. Awake and sleepelectroencephalograms were characterized by disorga-nized background activity and burst of generalizedrhythmic slowing without any epileptogenic activity.Electron microscopy of the buffy coat and skin biopsyshowed fingerprint profiles in the lysosomal storagematerial in the lymphocytes and skin cells. Polymerasechain reaction (PCR) test for the common deletion (1.02kb on the genomic level) showed (Fig. 1) one 2.3-kbband in the affected individual, who is homozygous(line 4), and two bands 2.3 and 3.3 kb in the mother(line 3) and maternal grandmother (line 2). The pater-nal grandmother does not carry the 1.02-kb deletion.She shows only one 3.3-kb band (line 1).

During the next two months, the patient had twoother seizure episodes and was treated with phenytoin.He has been followed on a monthly basis. Six monthsafter the diagnosis of JNCL was made, he showed somedeterioration in his cognitive status. His seizures arenot well controlled with anticonvulsant medication.

MATERIALS AND METHODS

Histologic and ultrastructural studies for diagnosisof NCL have been described previously [Taschner etal., 1995]. PCR amplification of the common 1.02-kbdeletion was conducted by using the PCR method.Briefly, 2.5 to 5 ng of genomic DNA that had been ex-tracted with a Puregene kit (Gentra, Minneapolis, MN)from either blood or cultured lymphoblasts was placedin a 0.2-ml thin-walled PCR tube and mixed with 9.5

ml of reaction mixture containing 1 × Taq extenderbuffer 20 mM Tris-HCl (pH 8.8), 10 mM KCl, 10 mM(NH4)2SO4, 2 mM MgSO4, 0.1% Triton X-100, 100 ngBSA, 0.2 mM dNTPs, 25 ng each forward and reverseprimers, 5.0 units of AmpliTaq DNA polymerase (Per-kin-Elmer, Norwalk, CT), and 5 units of Taq extenderPCR additive (Stratagene, La Jolla, CA). The amplifi-cation was carried out in a PTC-100 thermocycler (MJResearch, Inc., Watertown, MA) or PE-9600 (Perkin-Elmer) with denaturing at 94°C for 4 min, followed by30 cycles of 0.5 min at 94°C and 2.5 min at 72°C. Thelast annealing/extension was 10 min at 72°C. The PCRproduct was separated by electrophoresis through 0.8%SeaKem LE agarose (FMC BioProducts, Rockland,ME), with a 1-kb ladder (Gibco-BRL, Gaithersburg,MD) as a marker.

DISCUSSION

To date, the Batten Disease Registry lists 731 NClcases in the United States; JNCL comprised 341 of the731 cases. Detailed clinicopathologic data togetherwith pedigrees are available on 191 cases. Apparently,JNCL is the most common form of NCL. Clinicopatho-logic analysis of these 191 cases resulted in 151 typicaland 40 atypical presentations. The typical cases havevisual deterioration as the first clinical symptom withonset at 5 to 7 years of age, which is followed by im-paired cognitive function and cerebral signs. Finger-print inclusions are characteristic of typical JNCL. Us-ing molecular genetic techniques, PCR showed a 1.02-kb deletion either in both alleles (homozygous) or in asingle allele (heterozygous).

The clinical presentation of our case is typical for ageof onset of JNCL. To the best of our knowledge, thispatient is the first African-American child in whomelectron microscopic study showed the typical finger-print profile in lysosomes and PCR results with the1.02 kb-deletion in both alleles confirmed the clinicaldiagnosis [Wisniewski et al., 1992; Taschner et al.,1995].

REFERENCESDyken P, Wisniewski KE (1995): Classification of the neuronal ceroid li-

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Goebel HH (1995): The neuronal ceroid lipofuscinoses. J Child Neurol 10:424–437.

Taschner PEM, De Vas N, Catsman-Berrevoets CE, Van Duinen SG, Lind-hout D (1995): Application of chromosome 16 markers in the differen-tial diagnosis of neuronal ceroid lipofuscinosis. Am J Med Genet 57:338–343.

Wisniewski KE, Rapin I, Heaney-Kieran J (1988): Clinico-pathologicalvariability in the childhood neuronal ceroid lipofuscinoses and newobservations on glycoprotein abnormalities. Am J Med Genet Suppl5:27–46.

Wisniewski KE, Kida E, Patxot OF, Connell F (1992): Variability in theclinical and pathological findings in the neuronal ceroid lipofuscinoses:Review of data and observations. Am J Med Genet 42:525–532.

Fig. 1. PCR shows one 2.3-kb band in a homozygous individual (line 4)and two bands, 2.3 and 3.3 kb, in mother (line 3) and maternal grand-mother (line 2). The paternal grandmother does not carry the 1.02-kbdeletion, showing only one 3.3-kb band (line 1). M 4 marker (see text).

336 Inan et al.