Juvenile‐onset spinal muscular atrophy caused by compound heterozygosity for mutations in the <i>HEXA</i> gene

Navon, Ruth; Khosravi, Rami; Melki, Judith; Drucker, Liat; Fontaine, Bertrand; Turpin, Jean‐Claude; N'Guyen, Bathein; Fardeau, Michel; Rondot, Pierre; Baumann, Nicole

doi:10.1002/ana.410410512

Cited by 32 publications

(9 citation statements)

References 41 publications

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“…However, this mechanism is unlikely as LAMP2 precursors were not increased in plt mice. Together, because abnormal lysosomal storage has been shown to cause motor neuron degeneration (Bronson et al, 1993;Cook et al, 1995;Navon et al, 1997;Liu et al, 1999), lysosomal storage found in our study may serve as a potential mechanism contributing to motor neuron degeneration in Fig4 deficiency.…”

Section: Discussionsupporting

confidence: 51%

Distinct pathogenic processes between Fig4-deficient motor and sensory neurons

Katona

Zhang

Bai

et al. 2011

European Journal of Neuroscience

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Loss of function of the FIG4 gene causes Charcot-Marie-Tooth disease (CMT)-4J with many features also found in motor neuron disease (MND). Mechanisms for the degeneration are unknown. We investigated this using Fig4-deficient pale tremor (plt) mice, a mouse model of CMT4J. Ultrastructural studies in sensory neurons of dorsal root ganglion (DRG) confirmed abundant vacuoles with membrane disruption. The vacuoles became detectable as early as postnatal day 4 in the DRG. However, the vacuoles were absent or minimal in the spinal motor neurons or cortical neurons in 2- to 5-week-old plt mice. Instead, a large number of electron-dense organelles, reminiscent of those in lysosomal storage disorders, accumulated in the motor neurons, but not in the sensory neurons of DRG. This accumulation was associated with increased levels of lysosomal proteins, such as LAMP2 and NPC1, but not mannose-6-phosphate receptor, an endosomal protein that is usually excluded from the lysosomes. Our results suggest that Fig4 deficiency affects motor neurons differently from sensory neurons by mechanisms involving excessive retention of molecules in lysosomes or disruption of vacuolated organelles. These two distinct pathological changes may contribute to neuronal degeneration.

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Section: Discussionsupporting

confidence: 51%

Distinct pathogenic processes between Fig4-deficient motor and sensory neurons

Katona

Zhang

Bai

et al. 2011

European Journal of Neuroscience

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“…Clinical information about the symptoms at onset and its progression until the diagnosis was gathered retrospectively from parents through a detailed clinical protocol. * Refs 1,8,9,[11][12][13][14]18,20,22,. …”

Section: Methodsmentioning

confidence: 99%

“…7 Juvenile or subacute and the adult, also called late-onset or chronic, subtypes of this condition present later in childhood or in adulthood and progress more slowly. 1,[8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] The juvenile and adult forms of GM2 gangliosidosis differ from each other primarily by the impact of the disease on intelligence, which is minimal through much of the course of the adult or chronic variant.Several case reports and a small number of case series have been reported. 11,13,20,21 However, few studies have provided accurate descriptions of the natural clinical course of jGM2 in larger groups of patients.…”

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confidence: 99%

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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“…For example, in a group of lysosomal storage disorders known as the GM2 gangliosidoses, patients may have a deficiency of a lysosomal hydrolase (β-hexosaminidase). These patients present with clinical features of spinal muscular atrophy that primarily result from the degeneration of spinal motor neurons (Navon et al , 1997). Furthermore, the knockout of β-hexosaminidase in mice also results in the abnormal lysosomal storage of glycosphingolipid that accompanies neuronal degeneration, including damage to spinal motor neurons (Liu et al , 1999).…”

Section: The Lysosomal Pathology Of Fig4 Deficiency: Implications Formentioning

confidence: 99%

Fig4 deficiency: A newly emerged lysosomal storage disorder?

Martyn

2013

Progress in Neurobiology

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FIG4 (Sac3 in mammals) is a 5’-phosphoinositide phosphatase that coordinates the turnover of phosphatidylinositol-3,5-bisphosphate (PI(3,5)P2), a very low abundance phosphoinositide. Deficiency of FIG4 severely affects the human and mouse nervous systems by causing two distinct forms of abnormal lysosomal storage. The first form occurs in spinal sensory neurons, where vacuolated endolysosomes accumulate in perinuclear regions. A second form occurs in cortical/spinal motor neurons and glia, in which enlarged endolysosomes become filled with electron dense materials in a manner indistinguishable from other lysosomal storage disorders. Humans with a deficiency of FIG4 (known as Charcot-Marie-Tooth disease type 4J or CMT4J) present with clinical and pathophysiological phenotypes indicative of spinal motor neuron degeneration and segmental demyelination. These findings reveal a signaling pathway involving FIG4 that appears to be important for lysosomal function. In this review, we discuss the biology of FIG4 and describe how the deficiency of FIG4 results in lysosomal phenotypes. We also discuss the implications of FIG4/PI(3,5)P2 signaling in understanding other lysosomal storage diseases, neuropathies, and acquired demyelinating diseases.

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Juvenile‐onset spinal muscular atrophy caused by compound heterozygosity for mutations in the HEXA gene

Cited by 32 publications

References 41 publications

Distinct pathogenic processes between Fig4-deficient motor and sensory neurons

Distinct pathogenic processes between Fig4-deficient motor and sensory neurons

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

Fig4 deficiency: A newly emerged lysosomal storage disorder?

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