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1.
Clin Genet ; 93(2): 255-265, 2018 02.
Article in English | MEDLINE | ID: mdl-28653766

ABSTRACT

Biallelic mutations in SLC25A46, encoding a modified solute transporter involved in mitochondrial dynamics, have been identified in a wide range of conditions such as hereditary motor and sensory neuropathy with optic atrophy type VIB (OMIM: *610826) and congenital lethal pontocerebellar hypoplasia (PCH). To date, 18 patients from 13 families have been reported, presenting with the key clinical features of optic atrophy, peripheral neuropathy, and cerebellar atrophy. The course of the disease was highly variable ranging from severe muscular hypotonia at birth and early death to first manifestations in late childhood and survival into the fifties. Here we report on 4 patients from 2 families diagnosed with PCH who died within the first month of life from respiratory insufficiency. Patients from 1 family had pathoanatomically proven spinal motor neuron degeneration (PCH1). Using exome sequencing, we identified biallelic disease-segregating loss-of-function mutations in SLC25A46 in both families. Our study adds to the definition of the SLC25A46-associated phenotypic spectrum that includes neonatal fatalities due to PCH as the severe extreme.


Subject(s)
Mitochondrial Proteins/genetics , Motor Neuron Disease/genetics , Olivopontocerebellar Atrophies/genetics , Phosphate Transport Proteins/genetics , Alleles , Female , Humans , Infant , Infant, Newborn , Loss of Function Mutation/genetics , Male , Mitochondrial Dynamics/genetics , Motor Neuron Disease/mortality , Motor Neuron Disease/physiopathology , Mutation , Olivopontocerebellar Atrophies/mortality , Olivopontocerebellar Atrophies/physiopathology , Phenotype
2.
Neurology ; 48(2): 384-93, 1997 Feb.
Article in English | MEDLINE | ID: mdl-9040727

ABSTRACT

A systematic review of the neurologic literature identified 433 cases of pathologically proven multiple system atrophy over a 100-year period. Earlier case reports included patients younger in age with more frequent cerebellar involvement. Mean age of onset was 54.2 years (range 31 to 78) and survival was 6.2 years (range 0.5 to 24). Survival analysis showed a secular trend from a median duration of 4.9 years for publications between 1887 and 1970 to 6.8 years between 1991 and 1994. Older age of onset was associated with shorter survival; the hazard ratio for patients with onset after 60 years was 1.8 (95% CI 1.4 to 2.3) compared with patients between 31 and 49 years. Cerebellar features were associated with marginally increased survival (6.1 years versus 5.4 years; p = 0.04). There were no difference in survival according to gender, parkinsonian, or pyramidal features or whether the patient was classified as striatonigral degeneration or olivopontocerebellar atrophy type. These results demonstrate the poor prognosis for patients with multiple system atrophy but may be biased toward the worst cases. Future research needs to recruit more representative samples.


Subject(s)
Brain Diseases/mortality , Corpus Striatum , Olivopontocerebellar Atrophies/mortality , Adult , Aged , Atrophy , Autonomic Nervous System Diseases/mortality , Autonomic Nervous System Diseases/pathology , Brain Diseases/pathology , Cerebellar Diseases/mortality , Cerebellar Diseases/pathology , Female , Humans , Male , Middle Aged , Olivopontocerebellar Atrophies/pathology , Parkinson Disease/mortality , Parkinson Disease/pathology
3.
J Neurol ; 243(5): 401-4, 1996 May.
Article in English | MEDLINE | ID: mdl-8741080

ABSTRACT

The various clinical features of multiple system atrophy (MSA) make the diagnosis of the disease difficult, especially in its early stages, when signs of differentiated neuroanatomical system involvement have not yet appeared. Mortality studies may be affected by the variability of the diagnostic criteria and selection bias. We used strict clinical and MRI criteria to diagnose MSA in 59 patients. Patients with parkinsonian and cerebellar onset were compared. Median survival time from the onset of the first motor symptom was 7.5 years. Our results indicated a trend (P = 0.09) for the Northwestern University Disability Scale score to correlate with mortality, but we failed to find other characteristics identifying subgroups or predictors for survival.


Subject(s)
Corpus Striatum/physiology , Nerve Degeneration/physiology , Olivopontocerebellar Atrophies/mortality , Shy-Drager Syndrome/mortality , Substantia Nigra/physiology , Adult , Aged , Autonomic Nervous System Diseases/etiology , Corpus Striatum/pathology , Disease Progression , Female , Humans , Male , Middle Aged , Olivopontocerebellar Atrophies/complications , Olivopontocerebellar Atrophies/pathology , Parkinson Disease/etiology , Prognosis , Retrospective Studies , Shy-Drager Syndrome/complications , Shy-Drager Syndrome/pathology , Substantia Nigra/pathology , Survival Rate
4.
Intern Med ; 33(6): 321-5, 1994 Jun.
Article in English | MEDLINE | ID: mdl-7919616

ABSTRACT

We investigated the survival of patients with multiple system atrophy (MSA) in a follow-up study of 59 patients admitted to Nagoya University Hospital between 1976 and 1991. They consisted of 24 patients with olivopontocerebellar atrophy (OPCA), 25 with Shy-Drager syndrome (SDS) and 10 with striatonigral degeneration (SND). The mean age at onset was 54 years, the 3-year survival rate from onset was 90%, and the 6-year survival rate was 54%. Comparison of survival curve by clinical type revealed poorer survival in SDS and SND than in OPCA cases. Although in OPCA, SND and SDS the pathological alterations of the central nervous system are known to be very similar, characterized as MSA, the present study suggests that the earlier and the more severe the involvement of the autonomic nervous system, and to a lesser extent the striatonigral system, the poorer the prognosis may be.


Subject(s)
Brain Diseases/mortality , Olivopontocerebellar Atrophies/mortality , Shy-Drager Syndrome/mortality , Adult , Age Factors , Age of Onset , Aged , Corpus Striatum , Female , Humans , Male , Middle Aged , Prognosis , Retrospective Studies , Substantia Nigra , Survival Rate
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