Early and late manifestations of neuropathy due to HSPB1 mutation in the Jewish Iranian population.

OBJECTIVE: Mutations in the HSPB1 gene are associated with a distal hereditary motor neuropathy type 2 (dHMN2) or Charcot-Marie-Tooth disease type 2F (CMT2F), usually with autosomal dominant inheritance. This study aimed to describe the phenotype of the HSPB1 c.407G>T (p.Arg136Leu) mutation at early and late stages of the disease course. METHODS: We identified this mutation (previously reported in patients from Italy) in a heterozygous state, among 14 individuals from eight families of Jewish Iranian descent. The clinical, electrophysiological and ultrasonographic features were evaluated during early (less than 5 years, N = 9) or late disease course (N = 5). RESULTS: The majority of subjects were males with a mean age at onset of 43.4 years (range 21-67). Common initial symptoms were gait imbalance, distal (often asymmetric) lower limb weakness and feet numbness. Neurological examination in early disease course showed distal lower extremity weakness in nearly all cases, and absent Achilles tendon reflex in about half. A minority had distal loss of pain, vibration or position sensation. These findings were more prevalent in late disease stage. Electrodiagnostic studies demonstrated a length-dependent axonal motor neuropathy, with typical preferential involvement of the tibial nerve. Muscle ultrasound showed a corresponding length-dependent increase of homogeneous echo-intensity, most noticeably in the gastrocnemius. One patient had a dual diagnosis of CMT2F and CMT2W. INTERPRETATION: The HSPB1 c.407G>G (p.Arg136Leu) mutation causes an adult-onset, predominantly motor, axonal neuropathy in individuals of Jewish Iranian descent. Variable manifestations are noticed, and sensory involvement is more prominent in prolonged disease duration.

A single center experience with publicly funded clinical exome sequencing for neurodevelopmental disorders or multiple congenital anomalies.

Exome sequencing (ES) is an important diagnostic tool for individuals with neurodevelopmental disorders (NDD) and/or multiple congenital anomalies (MCA). However, the cost of ES limits the test's accessibility for many patients. We evaluated the yield of publicly funded clinical ES, performed at a tertiary center in Israel, over a 3-year period (2018-2020). Probands presented with (1) moderate-to-profound global developmental delay (GDD)/intellectual disability (ID); or (2) mild GDD/ID with epilepsy or congenital anomaly; and/or (3) MCA. Subjects with normal chromosomal microarray analysis who met inclusion criteria were included, totaling 280 consecutive cases. Trio ES (proband and parents) was the default option. In 252 cases (90.0%), indication of NDD was noted. Most probands were males (62.9%), and their mean age at ES submission was 9.3 years (range 1 month to 51 years). Molecular diagnosis was reached in 109 probands (38.9%), mainly due to de novo variants (91/109, 83.5%). Disease-causing variants were identified in 92 genes, 15 of which were implicated in more than a single case. Male sex, families with multiple-affected members and premature birth were significantly associated with lower ES yield (p < 0.05). Other factors, including MCA and coexistence of epilepsy, autism spectrum disorder, microcephaly or abnormal brain magnetic resonance imaging findings, were not associated with the yield. To conclude, our findings support the utility of clinical ES in a real-world setting, as part of a publicly funded genetic workup for individuals with GDD/ID and/or MCA.