Spinal and bulbar muscular atrophy (SBMA) is an X-linked recessive motor neuron disease characterized by slowly progressive weakness and atrophy of proximal limbs and bulbar muscles. To assess the genotype-phenotype correlation in Chinese patients, we identified 155 patients with SBMA and retrospectively examined available data from laboratory tests and neurophysiological analyses. Correlations between genotype and phenotype were analyzed. There was an inverse correlation between the length of CAG repeats and age at first muscle weakness (p<0.0001). The serum creatine kinase level showed a significant inverse correlation with disease duration and the age at examination (p=0.019 and p=0.004, respectively). Unlike previous classification of motor- and sensory-dominant phenotypes, all findings of nerve conduction, except the amplitudes of median nerve compound motor action potential, were positively correlated to the length of CAG repeats. A significant decline in sensory nerve action potential amplitudes may assist differential diagnosis of SBMA.

/pdf/genotype-phenotype-correlation-in-chinese-patients-with-auf8oueen4.pdf

Genotype-phenotype correlation in Chinese patients with spinal and bulbar muscular atrophy.

OBJECTIVE Spinal and bulbar muscular atrophy (SBMA) is a slowly progressive disease with weakness of bulbar and extremity muscles. There is no curative treatment for the disease, but several clinical trials have been conducted over the past years. The results from these trials have uncovered a great need to develop quantitative, reliable outcome measures. In this study, we prospectively investigated disease progression over 18 months in 29 patients with genetically confirmed SBMA, using quantitative outcome measures, including Dixon magnetic resonance imaging (MRI). METHODS We used MRI to assess changes in muscle fat content and stationary dynamometry to assess changes in muscle strength. Disease progression was also investigated with the SBMA functional rating scale, bulbar rating scale, 6-minute walk test, and blood samples, among others. RESULTS Mean muscle fat content, muscle strength in knee extensors, handgrip strength, walking distance, and creatinine levels changed significantly. Mean muscle fat content increased by 2 ± 1.25%, and knee extension strength decreased from 83 ± 60 to 76 ± 56Nm, handgrip strength from 31 ± 13 to 29 ± 13kg, walking distance from 362 ± 216 to 336 ± 219m, and creatinine level from 58 ± 21 to 54 ± 20 μmol/l. Functional rating scores did not change. INTERPRETATION The present study demonstrates a slow and steady disease progression in SBMA. Dixon MRI detected increases in muscle fat content in all investigated muscles and is therefore a suitable candidate for an outcome measure in natural history or treatment studies in SBMA. The 6-minute walk test and handgrip strength also seem to be reliable outcome measures for SBMA. Ann Neurol 2018;84:762-773.

Disease progression and outcome measures in spinobulbar muscular atrophy

BACKGROUND AND OBJECTIVE Hereditary spastic paraplegia (HSP) is a heterogeneous neurodegenerative disorder with lower-limb spasticity and weakness. Different patterns of inheritance have been identified in HSP. Most autosomal-dominant HSPs (AD-HSPs) are associated with mutations of the SPAST gene (SPG4), leading to a pure form of HSP with variable age-at-onset (AAO). Anticipation, an earlier onset of disease, as well as aggravation of symptoms in successive generations, may be correlated to SPG4. Herein, we suggested that anticipation might be a relatively common finding in SPG4 families. METHODS Whole-exome sequencing was done on DNA of 14 unrelated Iranian AD-HSP probands. Data were analyzed, and candidate variants were PCR-amplified and sequenced by the Sanger method, subsequently checked in family members to co-segregation analysis. Multiplex ligation-dependent probe amplification (MLPA) was done for seven probands. Clinical features of the probands were recorded, and the probable anticipation was checked in these families. Other previous reported SPG4 families were investigated to anticipation. RESULTS Our findings showed that SPG4 was the common subtype of HSP; three families carried variants in the KIF5A, ATL1, and MFN2 genes, while five families harbored mutations in the SPAST gene. Clinical features of only SPG4 families indicated decreasing AAO in affected individuals of the successive generations, and this difference was significant (p-value <0.05). CONCLUSION It seems SPAST will be the first candidate gene in families that manifests a pure form of AD-HSP and anticipation. Therefore, it may be a powerful situation of genotype-phenotype correlation. However, the underlying mechanism of anticipation in these families is not clear yet.

Anticipation Can Be More Common in Hereditary Spastic Paraplegia with SPAST Mutations Than It Appears.

Objective Hereditary spastic paraplegias (HSP) is a clinically and genetically heterogeneous group of neurodegenerative disorders. We describe the genetic and clinical features of a cohort of five HSP families from central-southern China. Methods Using targeted exome-sequencing technology, we investigated the genetic and clinical features in five HSP families. We reviewed the clinical histories of these patients as well as the molecular and functional characterization of the associated gene variants. We also performed functional analysis of an intron variant of SPAST in vitro. Results We identified a known SPAST mutation (p.Pro435Leu) in a family with autosomal dominant HSP (AD-HSP) and four novel variants in two HSP families and a sporadic case. These identified four novel variants included a variant in SPG11 (p.Val1979Ter), two variants in B4GALNT1 (p.Ser475Phe and c.1002 + 2 T > G), and a splicing site variant in SPAST (c.1245+5G>A). Minigene analysis of the splicing variant in SPAST (c.1245+5G>A) revealed that the mutation resulted in mRNAs with a loss of exon 9. The SPG4 family carrying c.1245+5G>A variant in SPAST exhibited genetic anticipation, with a decreased age at onset and increased severity in successive generations. The proband with p.Val1979Ter variant in SPG11 showed characteristic clinical features of early-onset, severe spasticity, and corpus callosum atrophy which were highly suggestive of the diagnosis of SPG11-associated HSP. Conclusions Our findings strongly support variable phenotype of B4GALNT1-related SPG26 and also expand the clinical and mutation spectrum of HSP caused by mutations in SPAST, SPG11, and B4GALNT1. These results will help to improve the efficiency of early diagnosis in patients clinically suspected of HSP.

/pdf/the-investigation-of-genetic-and-clinical-features-in-3hb1ro5dzs.pdf

The investigation of genetic and clinical features in patients with hereditary spastic paraplegia in central-Southern China

Spastin mutation screening in Chinese patients with pure hereditary spastic paraplegia

Clinical and genetic analysis of four Taiwanese families with autosomal dominant hereditary spastic paraplegia

Long-term follow-up of spinal and bulbar muscular atrophy in Taiwan.

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Clinical and genetic analysis of four Taiwanese families with autosomal dominant hereditary spastic paraplegia

Long-term follow-up of spinal and bulbar muscular atrophy in Taiwan.