Cherry Red Spot-myoclonus Syndrome Research Articles

Sialidoses.

Sialidoses are autosomal recessive disorders caused by NEU1 gene mutations and are classified on the basis of their phenotype and onset age. Sialidosis type II, with infantile onset, has a more severe phenotype characterized by coarse facial features, hepatomegaly, dysostosis multiplex, and developmental delay while patients with the late and milder type, known as "cherry red spot-myoclonus syndrome" develop myoclonic epilepsy, visual impairment and ataxia in the second or third decade of life. The diagnosis is usually suggested by increased urinary bound sialic acid excretion. We recently described genetically diagnosed patients with a specially mild phenotype, no retinal abnormalities and normal urinary sialic acid. This observation suggests that genetic analysis or the demonstration of the neuraminidase enzyme deficiency in cultured fibroblasts are needed to detect and diagnose mildest phenotypes.

Pitfalls in Diagnosing Neuraminidase Deficiency: Psychosomatics and Normal Sialic Acid Excretion.

Neuraminidase deficiency (mucolipidosis I, sialidosis types I and II, cherry-red spot myoclonus syndrome) is a lysosomal storage disorder with an expanding clinical phenotype. Here, we report the striking diagnostic history of late-onset neuraminidase deficiency in two sisters, currently aged 14 (patient 1) and 15 (patient 2).Patient 1 was referred for evaluation of her vision after a traffic accident. During this examination, nummular cataract, macular cherry-red spot, and optic nerve atrophy were seen. Furthermore, tremors were noticed in her arms and legs. This combination suggested a lysosomal storage disorder. Her family history revealed an older sister, patient 2, who had a long history of unexplained neurologic symptoms; she was under unsuccessful treatment for conversion disorder. Patient 2 showed identical ophthalmological findings. In retrospect, she had presented with avascular osteonecrosis of the right femur head at age 9.Urinary oligosaccharide patterns and enzyme activity revealed neuraminidase deficiency in both patients. Urinary-bound sialic acid levels were normal. Sequencing of NEU1 demonstrated two known compound heterozygous mutations (c.1195_1200dup p.His399_Tyr400dup; c.679G>A, p.Glu227Arg).The substantial time window between onset of typical symptoms and diagnosis in patient 2 suggests inadequate awareness of lysosomal storage disorders among clinicians. Of special interest is the observation that normal urinary sialic acid levels do not exclude neuraminidase deficiency. Urinary oligosaccharide screening is essential to diagnosis in such cases. In addition, patient 2 is the fourth case in the literature with a history of femur head necrosis. Bone defects might therefore be an early manifestation of late-onset neuraminidase deficiency.

Chaperone-mediated gene therapy with recombinant AAV-PPCA in a new mouse model of type I sialidosis

The lysosomal storage disease sialidosis is caused by a primary deficiency of the sialidase N-acetyl-α-neuraminidase-1 (NEU1). Patients with type I sialidosis develop an attenuated, non-neuropathic form of the disease also named cherry red spot myoclonus syndrome, with symptoms arising during juvenile/ adult age. NEU1 requires binding to its chaperone, protective protein/cathepsin A (PPCA), for lysosomal compartmentalization, stability and catalytic activation. We have generated a new mouse model of type I sialidosis that ubiquitously expresses a NEU1 variant carrying a V54M amino acid substitution identified in an adult patient with type I sialidosis. Mutant mice developed signs of lysosomal disease after 1year of age, predominantly in the kidney, albeit low residual NEU1 activity was detected in most organs and cell types. We demonstrate that the activity of the mutant enzyme could be effectively increased in all systemic tissues by chaperone-mediated gene therapy with a liver-tropic recombinant AAV2/8 vector expressing PPCA. This resulted in clear amelioration of the disease phenotype. These results suggest that at least some of the NEU1 mutations associated with type I sialidosis may respond to PPCA-chaperone-mediated gene therapy.

Activated sialidase activity in transformed lymphocytes by Epstein-Barr (EB) virus of sialidosis type I (cherry-red spot-myoclonus syndrome)

We report a new Japanese family of sialidosis type I. The sialidase activity was deficient in the lymphocytes of 2 patients (6.8% (sister) and 12.5% (brother) of control mean). However, surprisingly, using the transformed lymphocytes by EB virus, this activity was activated to 51.7% (sister) and 49.5% (brother) of control mean, respectively. Although the mechanism for this activation was not known, we discussed the possible mechanisms for this phenomenon.

Cherry-Red Spot Myoclonus Syndrome (Type I Sialidosis)

The authors report the sequence of the clinical symptoms in type I sialidosis or cherry-red spot myoclonus syndrome, derived from the cases personally observed and from the literature. They also report neuropathological and neurochemical data. A serial EEG study in a case shows the tendency to a progressive deregulation of cerebral electric activity. Therapeutic attempts to reduce myoclonus, which is one of the more disabling symptoms in this syndrome, are described.

P26 Multimodality evoked potentials and EEG in a case of cherry red spot myoclonus syndrome

P26 Multimodality evoked potentials and EEG in a case of cherry red spot myoclonus syndrome

Neuraminidase activities in sialidosis and mucolipidosis

Defects of neuraminidase activities towards sialyloigosaccharides in fibroblasts and leucocytes and enhanced excretion of sialyloligosaccharides in urine were shown in patients with adult type sialidosis with partial deficiency of β-galactosidase and cherry red spot-myoclonus syndrome. No differences in their neuraminidase residual levels and urinary excretion patterns on thin-layer chromatography were found between these two disorders. In mucolipidosis II and III patients, the neuraminidase activities towards sialyloligosaccharides were almost normal in leucocytes, although decreased in fibroblasts. The discrepancy of neuraminidase activities towards 2 →3 and 2 →6 sialyloligosaccharide isomers was not noticed in all cases.

Abnormal pattern electroretinograms with macular cherry-red spots: evidence for selective ganglion cell damage.

A macular cherry red spot is a strikingly visible abnormality indicating storage of an abnormal metabolic product by the retinal ganglion cells. The flash and pattern electroretinograms (ERG) and visual evoked potentials (VEP) of a patient with the cherry-red spot-myoclonus syndrome, a sialidosis due to neuraminidase deficiency, were studied. The flash ERG was normal but the pattern ERG had an abnormal waveform with a significantly attenuated p-q wave component. Corresponding flash VEPs were normal, but pattern VEPs were delayed. This case documents human evidence that the pattern ERG is organised in the ganglion cells whereas the flash ERG, as is well known, is generated in the distal retina.

Neuraminidase activity in the mucolipidoses (types I, II and III) and the cherry-red spot myoclonus syndrome

Two neuraminidase (EC 3.2.1.18) components, A and B, were distinguished in cultured skin fibroblasts on the basis of thermolability at 37°C. The more labile component (A) t 1 2 = 4.7–5.3 min at 37°C, comprises 66–90% of total neuraminidase activity when determined using sodium ( 4- methylumbelliferyl-α- d-N- acetylneuraminate ) (MU- α- N) as substrate. Activity was assayed at 0°C for 18 h instead of 37°C to fully determine both thermolabile and thermostable components. Diminished activity was noted in cultured fibroblasts from mucolipidoses I, II and III (MLI, MLII, MLIII) and the cherry-red spot myoclonus syndrome (CRSM) patients when assayed at both 0 and 37°C with either MU- α- N or each of a series of α(2 → 3)- and α(2 → 6)-linked N-acetylneuraminyl-oligosaccharides. Increased sensitivity and rapidity of analyses were achieved using MU- α- N as substrate in determining neuraminidase activity. Results from two obligate heterozygote MLI cell lines (14.5 and 8.0% of control activity) indicate that the MU- α- N substrate could be useful for heterozygote detection.

Cherry-Red Spot-Myoclonus Syndrome

A 21-year-old woman had typical clinical and biochemical findings of the cherry-red spot-myoclonus syndrome. She had 20/50 acuity in each eye, flutter-like ocular oscillations, rebound nystagmus, and transient vertical dissociation. Cherry-red maculas and optic atrophy were present. Although electroretinographic signals were normal, visual evoked potentials were almost absent. Levels of neuraminidase were significantly reduced in cultured ebroblasts from the patient and her parents, while lysosomal inclusions probably containing oligosaccharides were found in her conjunctival fibroblasts.

The cherry red spot-myoclonus syndrome: a newly recognized inherited lysosomal storage disease due to acid neuraminidase deficiency.

A newly discovered lysosomal storage disorder, apparently transmitted as an autosomal recessive trait, presents with cherry red spots in childhood, progressive debilitating myoclonus, insidious visual loss, and normal intelligence. Somatic and bony abnormalities are not evident clinically. Neuronal lipidosis and vacuolated Kuppfer cells are found upon tissue examination. The diagnosis can be most easily confirmed by chromatographic screening for urinary sialyloligosaccharides. The primary enzyme defect is a deficiency of an acid neuraminidase isoenzyme which cleaves sialyloligosaccharides. I discuss here the clinical phenotype in four patients, the chemical abnormality, the pathogenesis, the enzyme defect and the molecular genetics of this disorder.

567 THE CHERRY RED SPOT-MYOCLONUS SYNDROME DUE TO NEUR-1 AMINIDASE DEFICIENCY

The cherry red spotmyoclonus syndrome has been reported in at least 11 individuals in the past 20 years. The symptoms usually have their onset in the second decade of life and include macular cherry-red spots, myoclonus and increased deep tendon reflexes and no dementia. Recently neuraminidase deficiency has been documented in some of these patients. This report is of a.31 year old male with macular cherry-red spots, hyperreflexia and myoclonus (tremors and sudden quick jerks of both hands) without dementia. An older brother who had progressive myoclonus died at age 33 with myoclonic seizures. Homogenates of cultured fibroblasts from the proband exhibited a marked deficiency of neuraminidase activity. The neuraminidase activities in fibroblasts from the proband's parents and in two children of the proband were in the intermediate range. The cherry red spot-myoclonus syndrome is clinically distinct from Mucolipidosis I in which neuraminidase deficiency has also been reported.

Neuraminidase deficiency in the cherry red spot-myoclonus syndrome

Two patients with the cherry red spot-myoclonus syndrome excreted excessive quantities of sialylated oligosaccharides in urine. Skin fibroblasts from both patients had a severe deficiency of neuraminidase activity using α-L-N-acetylneuraminosyl-(2→6′) lactose and a sialylhexasaccharide from their urine as substrates. A less severe deficiency was found using 2-(3′ methoxyphenyl)-N-acetylneuraminic acid, fetuin, and α-L-N-acetylneuraminosyl-(2→3′) lactose as substrates. I propose that the primary enzyme defect in this autosomal recessive disorder is a deficiency of lysosomal neuraminidase.