SACS variants are a relevant cause of autosomal recessive hereditary motor and sensory neuropathy.

Mutations in the SACS gene have been initially reported in a rare autosomal recessive cerebellar ataxia syndrome featuring prominent cerebellar atrophy, spasticity and peripheral neuropathy as well as retinal abnormalities in some cases (autosomal recessive spastic ataxia of Charlevoix-Saguenay, ARSACS). In the past few years, the phenotypic spectrum has broadened, mainly owing to the availability and application of high-throughput genetic testing methods. We identified nine patients (three sib pairs, three singleton cases) with isolated, non-syndromic hereditary motor and sensory neuropathy (HMSN) who carried pathogenic SACS mutations, either in the homozygous or compound heterozygous state. None of the patients displayed spasticity or pyramidal signs. Ataxia, which was noted in only three patients, was consistent with a sensory ataxia. Nerve conduction and nerve biopsy studies showed mixed demyelinating and axonal neuropathy. Brain MRI scans were either normal or revealed isolated upper vermis atrophy of the cerebellum. Our findings confirm the broad clinical spectrum associated with SACS mutations, including pure polyneuropathy without characteristic clinical and brain imaging manifestations of ARSACS.

X-linked bulbospinal neuronopathy: Kennedy disease.

OBJECTIVE: To characterize the earliest symptoms of X-linked bulbospinal neuronopathy (Kennedy disease [KD]) during the course of the disease, including a definition of the age of onset. METHODS: We describe the earliest symptoms, signs on clinical investigation, electrophysiological and muscle biopsy specimen findings, and creatine kinase levels in 34 patients with KD. Correlations were made among the CAG-repeat length and clinical symptoms, age at onset, and the presence of electrophysiological and laboratory findings. RESULTS: Our findings indicate that the age at onset of KD is in adolescence which is earlier than previously thought. Most frequently early symptoms are gynecomastia, muscle pain, and premature muscular exhaustion. Weakness is not a typical initial symptom and is frequently found in distal limbs if present early. We found a correlation between the of number of CAG repeats and the age at onset of weakness but not to the age at onset of KD. Furthermore, no correlations were found between the occurrence of gynecomastia, tremor, increased creatine kinase levels, and additional myopathic changes in muscle biopsy specimens. CONCLUSIONS: Our data show that KD is a multisystem disorder with onset in adolescence. Because of the heterogeneity of clinical presentation and no correlation between the number of CAG repeats and most of the clinical hallmarks of KD, we suggest that other environmental or genetic factors contribute to the manifestation of specific organ systems in KD.