Progressive dystonia symptomatic of juvenile GM2 gangliosidosis

Nardocci, Nardo; Bertagnolio, B.; Rumi, V.; Angelini, Lucia

doi:10.1002/mds.870070113

Cited by 36 publications

(21 citation statements)

References 23 publications

(11 reference statements)

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“…Administration of AA in doses of 1 g/day or more resulted in a signi®cant and constant decrease of urinary BQA, the causative toxic metabolite, whereas the excretion of HGA could not be substantially reduced. This is in agreement with previous observations in two adult alkaptonuric patients treated with 10 g AA/day [3]. However, in two of the infants previously studied, AA doubled the amount of urinary HGA presumably by an eect on the immature p-hydroxyphenylpyruvic acid oxidase [3].…”

Section: Effects Of Ascorbic Acid and Low-protein Diet In Alkaptonuriasupporting

confidence: 90%

“…This is in agreement with previous observations in two adult alkaptonuric patients treated with 10 g AA/day [3]. However, in two of the infants previously studied, AA doubled the amount of urinary HGA presumably by an eect on the immature p-hydroxyphenylpyruvic acid oxidase [3].…”

Section: Effects Of Ascorbic Acid and Low-protein Diet In Alkaptonuriasupporting

confidence: 90%

“…He was in good health until 45 years of age when he developed clinical signs of alkaptonuric arthropathy. Additionally, his ears showed black pigmentation During each trial, AA, HGA and BQA acid were analysed regularly in plasma and/or 24 h urine samples by high-performance liquid chromatography [3].…”

Section: Effects Of Ascorbic Acid and Low-protein Diet In Alkaptonuriamentioning

confidence: 99%

“…Meek et al [2] and Nardocci et al [3] observed patients with the juvenile form of Tay-Sachs disease who showed a progressive generalized dystonia, combined with mental deterioration and behavioural disturbances. Some patients with the juvenile form of GM 2 -gangliosidosis types 0 and B presented with symptoms of cerebellar dysfunction [1,6].…”

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Progressive cerebellar ataxia in juvenile GM 2 -gangliosidosis type Sandhoff

Beck

Sieber

Goebel

1998

European Journal of Pediatrics

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Sir: The classical infantile forms of Tay-Sachs and Sandho disease (GM 2 -gangliosidosis types B and 0) exhibit a relatively uniform clinical picture characterized by early neurological deterioration leading to a decerebrate, vegetative state by the 2nd to 4th year of life. Late-onset forms, however, present a wide spectrum of clinical manifestations with a predominant involvement of one part of the CNS.We observed an 8-year-old girl with Sandho disease in whom severe ataxia was the leading symptom. Intention tremor and gait diculties arose from the 1st year of life. Clinical evaluation at the age of 8 years revealed a very shy girl who exhibited an ataxic gait and diculty in standing alone without support. There was a marked action tremor and dysdiadochokinesis of the hands which interfered with precise movements. Tendon re¯exes of the lower extremities were brisk with positive Babinski sign. Cranial nerve functions were normal; nystagmus was not observed. Fundoscopy was normal with no cherry-red macular spot. The EEG showed normal electrical activity without spike discharges. The child could speak and draw simple ®gures, but was unable to write. Liver and spleen were not enlarged. Correlating with the clinical presentation MRI revealed a marked cerebellar atrophy, whereas images of the cerebral hemispheres and thalamus did not reveal any pathological change (Fig. 1).The progressive clinical course suggested a lysosomal storage disorder. Several lysosomal enzymes were determined in the patientÔs serum and ®broblasts using arti®cial¯uorogenic substrates according to standard methods. A profound de®ciency of total hexosaminidase was detected in both the patientÔs serum (1.3 0.2 nmol/min/ml; normal range 19.2±51.2, median 28.9 nmol/min/ml, n 40) and ®broblasts (5.4 0.6 nmol/min/ mg protein; normal range 125±300, median 228 nmol/min/mg protein, n 35). Hexosaminidase A activity, as determined with the sulphated¯uorogenic substrate was also de®cient. The reference enzyme (b-glucuronidase) activity was in the normal range.

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Section: Effects Of Ascorbic Acid and Low-protein Diet In Alkaptonuriasupporting

confidence: 90%

Section: Effects Of Ascorbic Acid and Low-protein Diet In Alkaptonuriasupporting

confidence: 90%

Section: Effects Of Ascorbic Acid and Low-protein Diet In Alkaptonuriamentioning

confidence: 99%

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Progressive cerebellar ataxia in juvenile GM 2 -gangliosidosis type Sandhoff

Beck

Sieber

Goebel

1998

European Journal of Pediatrics

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“…The most common symptoms at onset were speech problems and developmental delay. Intellectual impairment, along with incoordination, † Refs 1,8,11,13,20,24,25,27,34,36,38,42,45,56,65,[68][69][70]74, and 91. ‡ Refs 1,20,25,27,29,34,38,42,56,74, and 91.…”

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The Natural History of Juvenile or Subacute GM2 Gangliosidosis: 21 New Cases and Literature Review of 134 Previously Reported

et al. 2006

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OBJECTIVE-Juvenile GM2 gangliosidosis is a group of inherited neurodegenerative diseases caused by deficiency of lysosomal β-hexosaminidase resulting in GM2 ganglioside accumulation in brain. The purpose of this study was to delineate the natural history of the condition and identify genotype-phenotype correlations that might be helpful in predicting the course of the disease in individual patients.METHODS-A cohort of 21 patients with juvenile GM2 gangliosidosis, 15 with the Tay-Sachs variant and 6 with the Sandhoff variant, was studied prospectively in 2 centers. Our experience was compared with previously published reports on 134 patients. Information about clinical features, β-hexosaminidase enzyme activity, and mutation analysis was collected.RESULTS-In our cohort of patients, the mean (±SD) age of onset of symptoms was 5.3 ± 4.1 years, with a mean follow-up time of 8.4 years. The most common symptoms at onset were gait disturbances (66.7%), incoordination (52.4%), speech problems (28.6%), and developmental delay (28.6%). The age of onset of gait disturbances was 7.1 ± 5.6 years. The mean time for progression Address correspondence to Joe T. R. Clarke, MD, PhD, Division of Clinical and Metabolic Genetics, Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8. joe.clarke@sickkids.ca. The authors have indicated they have no financial relationships relevant to this article to disclose. CIHR Author Manuscript CIHR Author Manuscript CIHR Author Manuscriptto becoming wheelchair-bound was 6.2 ± 5.5 years. The mean age of onset of speech problems was 7.0 ± 5.6 years, with a mean time of progression to anarthria of 5.6 ± 5.3 years. Muscle wasting (10.6 ± 7.4 years), proximal weakness (11.1 ± 7.7 years), and incontinence of sphincters (14.6 ± 9.7 years) appeared later in the course of the disease. Psychiatric disturbances and neuropathy were more prevalent in patients with the Sandhoff variant than in those with the TaySachs variant. However, dysphagia, sphincter incontinence, and sleep problems occurred earlier in those with the Tay-Sachs variant. Cerebellar atrophy was the most common finding on brain MRI (52.9%). The median survival time among the studied and reviewed patients was 14.5 years. The genotype-phenotype correlation revealed that in patients with the Tay-Sachs variant, the presence of R178H and R499H mutations was predictive of an early onset and rapidly progressive course. The presence of either G269S or W474C mutations was associated with a later onset of symptoms along with a more slowly progressive disease course.CONCLUSIONS-Juvenile GM2 gangliosidosis is clinically heterogeneous, not only in terms of age of onset and clinical features but also with regard to the course of the disease. In general, the earlier the onset of symptoms, the more rapidly the disease progresses. The Tay-Sachs and Sandhoff variants differed somewhat in the frequency of specific clinical characteristics. Speech deterioration progressed more rapidly than gait abnormalities in both the Tay-Sa...

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