Hereditary Spastic Paraplegia: Genetic Heterogeneity and Genotype-Phenotype Correlation

AbstractFucosidosis is an autosomal recessive disorder caused by a deficiency of alpha-L-fucosidase. Up to now 79 cases have been described and several others identified but not yet published. The higher incidence of the disease is in Italy, where nearly 20 patients have been identified. Fourteen disease-causing mutations have been detected and four of them, Q422X, G60D, E375X, P141fs are present in more than 70% of the forty patients studied. In Italian patients, only seven mutations have been described and P141fs and G60D mutations are present in more than 50% of the cases. The P141fs mutation is absent in other ethnic groups. It has been impossible to establish genotype-phenotype correlation so far and the clinical variability of the disease cannot be explained only by genetic heterogeneity.

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phenotypic and genetic heterogeneity of adult patients with hereditary spastic paraplegia from Serbia

Journal of the Neurological Sciences ◽

10.1016/j.jns.2019.10.329 ◽

2019 ◽

Vol 405 ◽

pp. 59-60

Author(s):

S. Peric ◽

V. Markovic ◽

E. De Vriendt ◽

A. Estrada-Cuzcano ◽

M. Svetel ◽

...

Keyword(s):

Genetic Heterogeneity ◽

Hereditary Spastic Paraplegia ◽

Adult Patients ◽

Spastic Paraplegia

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A p.Arg499His mutation in SPAST is associated with infantile-onset complicated spastic paraplegia: a case report and review of the literature

BMC Neurology ◽

10.1186/s12883-021-02478-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Haitian Nan ◽

Hiroshi Shiraku ◽

Tomoko Mizuno ◽

Yoshihisa Takiyama

Keyword(s):

Japanese Patient ◽

De Novo ◽

Complex Form ◽

Review Of The Literature ◽

Spastic Paraplegia ◽

Phenotype Correlation ◽

Spastic Paralysis ◽

Hereditary Spastic Paraplegias ◽

Genotype Phenotype Correlation ◽

Complicated Form

Abstract Background Spastic paraplegia type 4 (SPG4) is caused by mutations in the SPAST gene, is the most common form of autosomal-dominant pure hereditary spastic paraplegias (HSP), and is rarely associated with a complicated form that includes ataxia, epilepsy, and cognitive decline. To date, the genotype-phenotype correlation has not been substantially established for SPAST mutations. Case presentation We present a Japanese patient with infantile-onset HSP and a complex form with coexisting ataxia and epilepsy. The sequencing of SPAST revealed a de novo c.1496G > A (p.R499H) mutation. A review of the literature revealed 16 additional patients with p.R499H mutations in SPAST associated with an early-onset complicated form of HSP. We found that the complicated phenotype of patients with p.Arg499His mutations could be mainly divided into three subgroups: (1) infantile-onset ascending hereditary spastic paralysis, (2) HSP with severe dystonia, and (3) HSP with cognitive impairment. Moreover, the c.1496G > A mutation in SPAST may occur as a de novo variant at noticeably high rates. Conclusion We reviewed the clinical features of the patients reported in the literature with the p.Arg499His mutation in SPAST and described the case of a Japanese patient with this mutation presenting a new complicated form. Accumulating evidence suggests a possible association between infantile-onset complicated HSP and the p.Arg499His mutation in SPAST. The findings of this study may expand the clinical spectrum of the p.Arg499His mutation in SPAST and provide an opportunity to further study the genotype-phenotype correlation of SPG4.

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ACTB Mutations Analysis and Genotype–Phenotype Correlation in Becker’s Nevus

Biomedicines ◽

10.3390/biomedicines9121879 ◽

2021 ◽

Vol 9 (12) ◽

pp. 1879

Author(s):

Shangzhi Dai ◽

Huijun Wang ◽

Zhimiao Lin

Keyword(s):

Correlation Analysis ◽

Genetic Heterogeneity ◽

Chinese Patients ◽

Upper Limbs ◽

Phenotype Correlation ◽

Arrector Pili Muscle ◽

Genotype Phenotype Correlation ◽

Becker’S Nevus ◽

Recurrent Mutations

Becker’s nevus (BN) is a cutaneous hamartoma which is characterized by circumscribed hyperpigmentation with hypertrichosis. Recent studies have revealed that BN patients harbored postzygotic ACTB mutations, which were restricted to arrector pili muscle lineage. We screened for ACTB mutations in 20 Chinese patients with BN and found that recurrent mutations (c.C439A or c.C439T) in ACTB were detected in the majority of BN patients. However, more than 20% of the patients were negative for ACTB mutations, suggesting a possible genetic heterogeneity in Becker’s nevus. Interestingly, these mutations were also detected in dermal tissues outside the arrector pili muscle. We further performed genotype–phenotype correlation analysis, which revealed that lesions above the waistline, including the trunk above the anterior superior spine level, upper limbs and face, or covering more than 1% BSA were more likely to be positive for ACTB mutations. Altogether, our results provide further evidence of postzygotic ACTB mutations in BN patients and suggest a possible genotype–phenotype correlation of BN.

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