Choroideremia with leukoencephalopathy and arylsulfatase A pseudodeficiency

JOURNAL

OF THE

NEUROLOGICAL SCIENCES

ELSEVIER

Journal of the Neurological Sciences 138 (1996) 161- 164

Casereport

Choroideremia with leukoencephalopathy and arylsulfatase A pseudodeficiency Wataru Matsuyama a, Masaru Kuriyama b, Masanori Nakagawa a**, Hironobu Kanazawa a, Satoshi Takenaga a, Shinji Ijichi a, Mitsuhiro Osame a a Third Department b Second Department

of Internal of Internal

Medicine, Medicine,

Kagoshima Unirersi~ School of Medicine, Sakuragaoka 8-35-1, Kagoshima 890, Japan Fukui Medical UniL,er.si@, Shimoaizuki 23-3, Matsuokachou Yoshida Fukui 910-11, Japan

Received 3 1 October 1995; accepted 1 December 1995

Abstract A 33.year-old male patient was admitted to our hospital because of progressive gait disturbance and involuntary movement of the neck. He showed choroideremia, distal motor neuropathy, and leukoencephalopathy on T2-weighted brain magnetic resonance imaging (MRI). Choroideremia is a rare X-linked, progressive, degenerative disease of retina and choroid. There have been some reports of choroideremia patients with neurological complications. Recent studies have assigned its genetic locus to a small segment of Xq21.3 and it encodes a protein that resembles component A of rat Rab geranyl-geranyl transferase, a protein essential for cell function. This patient did not have the reported genetic abnormalities for choroideremia. Known disorders causing leukoencephalopathy were not detected except for a partial deficiency of arylsulfatase A (17.3% of normal controls in lymphocytes and 13.7% in fibroblasts). Deficiency of arylsulfatase A activity occurs in the late infantile, juvenile, and adult forms of metachromatic leukodystrophy (MLD) which is also an inherited disorder of myelin metabolism, but because of its unstability, it occurs in normal individuals and in patients with other neurological diseases. Consequently, we suspect that this patient had partial deficiency of arylsulfatase A and choroideremia as predisposing factors for white matter degeneration. Keywords:

Choroideremia; Pseudodeficiency of arylsulfatase A; Leukoencephalopathy

1. Introduction Choroideremia is an X-linked recessive disease which night blindness, visual field constriction, and eventual blindness, starting at an early age in affected males (McCulloch and McCulloch, 1948). Histological findings are characterized by degeneration of the choroid, retinal pigment epithelium, and the retina (Robin et al., 1966). Recent studies have indicated that the defective gene in choroideremia is mapped to chromosome Xq21 (Nussbaum et al., 1985) which encodes component A of Rab geranyl-geranyl transferase Geabra et al., 1992). Clinically, some cases of choroideremia have been associated with neurological manifestations including mental illness, deafness (Van den Bosch, 1959), convulsion, cerebellar ataxia, horizontal nystagmus (Nussbaum et al., 1987), causes progressive

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spastic paraparesis (Menon et al., 19891, peripheral neuropathy (Kawata et al., 19901, and Keams-Sayre syndrome (Herzberg et al., 1993). Metachromatic leukodystrophy (MLD) is characterized by accumulation of galactosyl sulfatide (cerebroside sulfate) in the white matter of the central nervous system and the peripheral nerves, and also within the kidney, gallbladder, and certain other visceral organs (Kolodony et al., 1995). In late infantile and juvenile forms, the earliest symptoms are gait disturbance, mental regression, and urinary incontinence, and these patients occasionally show blindness, loss of speech, quadriparesis, peripheral neuropathy and seizures. In most patients with adult MLD, behavior disturbances and dementia are the major presenting neurological manifestations. Deficiency of arylsulfatase A activity occurs in all forms of MLD. In this paper, we report a 33-year-old male patient with choroideremia associated with neurological manifestations, white matter degeneration on brain magnetic resonance imaging (MRI), and a partial deficiency of arylsulfatase A.

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2. Case report The patient, a 33-year-old male, had a normal birth and development but was always a slow runner in childhood. He attended elementary school without problems. At age 9, he noticed visual disturbance, which progressed slowly and he attended junior high school for the blind. At age 15, he had gait disturbance with muscle spasticity in the lower limbs, and could not run fast. At age 28, he had slowly progressing dystonic movement of the neck. He was the second of two children of non-consanguineous parents. No other member of his family or close relatives had similar symptoms. At age 33, he was admitted to our hospital because of progressive gait disturbance and dystonic movement of the neck. On physical examination, he was moderately obese with normal findings on chest and abdominal examinations. On neurological examination, he was slightly dull and depressive. His IQ was normal, and comprehension seemed good. Visual acuity was totally blind. Fundoscopic examination showed atrophy of the retina and choroid in both eyes and the findings were compatible for choroideremia (Fig. l), but without macular deposits. Ocular movement was full in all directions without nystagmus. No cornea1 opacity was detected by slit lamp examination. His speech was slightly dysarthric with stuttering. His neck showed involuntary dystonic movement with slow flexion and deflexion. There was diffuse muscular weakness, dominantly in distal parts of all four limbs. No fasciculation was noted. Muscle tonus was spastic. Reflexes were generally increased with bilateral Babinski reflexes. Poor coordination and intension tremor were noted on bilateral hands. Mild sensory paresthesia was detected in lower limbs. Routine hematological and laboratory studies were normal except creatine kinase level which was 103 mu/ml (normal, less than 50 mu/ml). Serum lactate and pyruvate levels were normal at rest, and were not abnormally increased after exercise. Both antibodies for human immunodeficiency virus type 1 (HIV-l) and human T lymphotropic virus type 1 (HTLV-1) were negative. Examina-

Fig. I. A white fundus, atrophy of retinal pigment epithelium, and scanty choroidal vessels characteristic of advanced choroideremia were observed on the right eye fundus.

tion of bone marrow revealed no vacuoles in the cells. Cerebrospinal fluid (CSF) examination disclosed normal pressure, sugar, and cell content. However, protein was markedly increased (305 mg/dl), and IgG content was also increased (36 mg/dl; normal, less than 5 mg/dl). Quantitative measurement of amino acids in serum and urine, and urinary organic acids analyzed by gas-liquid chromatography were normal. No increases in levels of very long chain fatty acids were found in the plasma sphingomyelin. Several lysosomal enzymes, a-galactosidase, P-galactosidase, cY-mannosidase, a-fucosidase, cyglucosidase, /3-gluculonidase, N-acetyl-P-glucosiaminidase, and arylsulfatase A, were assayed according to standard procedures using 4-methylumbelliferyl or p-nitrocatech01 conjugates as substrates in peripheral lymphocytes and cultured skin fibroblasts. The activities of arylsulfatase A were decreased in the lymphocytes (17.3% of controls) and fibroblasts (13.7%) from the patient compared with normal controls. His parents revealed moderately low activities on the lymphocytes (Table 1). There were no significant decreases in activities of the other 7 enzymes examined in the patient. Urinary oligosaccharides were isolated from the patient. Neutral and acid oligosaccharides were analyzed by thin-layer

Table 1 Lysosomal enzyme activities in lymphocytes and fibroblasts Lymphocytes Patient Father Mother Controls (n = 30) Fibroblasts Patient Controls (n = 4)

P-Gal

P-Hex

D-Man

P-Fuc

Ary.A

169.8 183+ 18.1

1740 1959 1363 1386* 163

36.8 44+2.1

54.5 44+8.2

13.1 40.5 32.7 75.6 k 19.8

-

4525 6035 + 883

-

-

89.7 654.2 + 100.1

Enzyme activities in controls were expressed as means f S.D.P-Gal; P-galactosidase, P-Hex; P-N-acetylglucosaminidase, P-fucosidase, Ary.A; arylsulfatase A.

o-Man; ol-mannosidase, P-Fuc;

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chromatography (TLC). No abnormal bands of neutral oligosaccharides or acidic sialyloligosaccharides were found on TLC in the patient. Urinary sediments were collected from 24-h urine by paper filtration, and total lipids were extracted with chloroform/methanol and analyzed by TLC. The major neutral lipids were ceramide monohexoside and ceramide dihexoside, and no accumulation of sulfatide was found in the patient urinary sediments. There were no abnormal findings by electrocardiography or echocardiography. Roentogenograms of the chest, skull, vertebrae and long bones showed normal configurations. An electroencephalogram showed diffuse slow and irregular background activity with low amplitude but no paroxysmal activity. Electromyogram (EMG) was consistent with slight neurogenic pattern with fibrillation potentials in the distal muscles of all four limbs. Nerve conduction studies showed normal motor conduction velocities with decreased compound motor action potentials (cMAP) on tibia1 nerves. Sensory nerve conduction velocities and somatosensory evoked potential were normal in the tibia1 nerve stimulation. Brain CT indicated marked diffuse periventricular low density with mild dilatation of ventricles, mild atrophy in the basal ganglia and brain stem, and moderate to low density of cerebellar white matter. T2 weighted brain MRI demonstrated diffuse and symmetrical high intensity signals in cerebral and cerebellar white matter regions (Fig. 2). Chromosomal analysis demonstrated a normal male karyotype. No deletion or translocation was detected in chromosomes. No mitochondrial DNA deletions were detected by Southern blot analysis and no known genetic abnormalities of the choroideremia gene at Xq21.3 were found.

Fig. 2. T2 weighted MRI of the brain (lower level) showed severe high intensity in periventricular white matter regions and in cerebellar white matter.

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Fig. 3. The numbers of large and small myelinated fibers were well preserved in sural nerve. Occasional fibers had thinner myelin compared with their axon diameters. Clusters of small myelinated fibers were noted rarely.

Pathological findings of biopsied sural nerve showed thinner myelin and a few clusters of small myelinated fibers. No accumulated materials were found in Schwann cells, pericytes, or epineural connective tissue elements (Fig. 3). Frozen biopsied specimens of the biceps brachii muscle showed mild myopathic changes with no abnormal changes in oxidative enzyme activity or ragged-red fibers.

3. Discussion The clinical and biochemical findings in this patient were characterized by choroideremia, progressive spastic paraparesis, involuntary movement of the neck, leukoencephalopathy detected by brain MRI, mild neuropathy and pseudodeficiency of arylsulfatase A. Choroideremia is an inherited disorder which causes chorioretinal degeneration, characterized by severe atrophy of the retinal and choroid layers in the extramacular regions. Recently, Seabra et al. reported that lymphoblasts from patients with choroideremia showed a marked de% ciency in the activity of Rab geranyl-geranyl transferase which transfers 20-carbon isoprenoid groups to cysteine residues in the Rab protein, a family of guanosine triphosphate (GTP)-binding proteins that regulate vesicular traffic (Seabra et al., 1993). Deletions in the central and 3’ parts of the choroideremia gene have been reported in patients with choroideremia (Merry et al., 1989). In this patient, however, we found no known deletions in this gene by Southern blot analysis. However, the existence of possible point mutations or new mutations of this gene could not be excluded, and the gene studied may not be the sole gene responsible for choroideremia. The patient showed decreased arylsulfatase A activities in lymphocytes and fibroblasts. However, MLD could not be diagnosed for this patient for the following reasons: (1) residual activity was relatively high; (2) no accumulation

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of sulfatides was found in the urine; (3) no cytoplasmic inclusion was observed in the biopsied sural nerve; and (4) the clinical manifestations also differed from those in the adult form of MLD. Other disorders causing leukodystrophy were also ruled out on the basis of clinical features and the results of laboratory examinations. Arylsulfatase A activity is occasionally deficient in some relatives of patients with MLD, in normal individuals, and in patients with other neurological diseases. These individuals do not have metachromatic deposits in peripheral nerve tissues, and their urinary sulfatide content is normal. They do not have MLD, nor are they in a preclinical stage of MLD. This phenomenon has been termed pseudodeficiency of arylsulfatase A (Kolodny and Flubarty, 19951, and the deficiency of the enzyme activity in these cases is due to a catalytically normal but unstable arylsulfatase A. The possibility that the pseudodeficiency of arylsulfatase A may confer in this patient a predisposition to leukodystrophy remains. The metabolic factors causing choroideremia and the disturbance of sulfatide metabolism may overlap each other and result in demyelination in the brain. Some cases of choroideremia have been associated with neurological manifestations including mental illness, deafness (Van den Bosch, 1959), convulsion, cerebellar ataxia, horizontal nystagmus (Nussbaum et al., 1987), spastic paraparesis (Menon et al., 1989), peripheral neuropathy (Kawata et al., 1990), and Kearns-Sayre syndrome (Herzberg et al., 1993). This patient is the first case of choroideremia with involuntary movement of the neck, distal motor neuropathy, and leukoencephalopathy. Disturbance of neuronal cell function might primarily occur in patients with choroideremia, because Rab is essential for cell function. Choroideremia might be phenotypically and genetically heterogeneous, and the disorder might show a wide clinical spectrum from isolated retinal and choroidal abnormalities to generalized neurological abnormalities. An additional metabolic disturbance to choroideremia might predispose patients to neuronal cell damage. We suggest that the present patient with choroideremia had pseudodeficiency of arylsulfatase A as a predisposing factor for white matter degeneration.

Acknowledgements We wish to thank Dr.Y. Mashima (Department of Ophthalmology, Keio University, School of Medcine) for studies of the choroideremia gene.

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