Clinical phenotypes
The probands are a 45-year-old male (III-38) and his 39-year-old sister (III-40), born to declared non-consanguineous parents from the same small village of Southern Italy (Calabria). The second-born child, who died at 5 in a car accident, developed normal language skills (Figure 1a). The siblings were affected by global developmental delay (walking >18 months), ataxia, intellectual disability, speech delay (first words at 5-6 years), focal drug-resistant epileptic seizures (by the age of 15) and progressive gait deterioration. Furthermore, they showed several craniofacial dysmorphisms, hypertrichosis, abdominal distention, and flatfoot (Table 1). Brain MRI in the brother showed bilateral mesial temporal sclerosis (documented when the patient was 35 years old) and clinodactyly of the 5th finger (Figure 1b). Both siblings achieved complete pubertal development. Metabolic tests (urinary amino and organic acids, lactate, pyruvate, ammonium), echocardiogram, audiometry, and first-level genetic screening (karyotyping, subtelomeric FISH) were normal. The proposita underwent bilateral cataract surgery at the age of 31.
The family history was remarkable for other neuromuscular diseases in the maternal side of the pedigree, whereas no extensive information was available for paternal relatives. Two cousins (daughters of a mother’s brother; III-1 and III-2) died of congenital muscular dystrophy at the age of 6 and 2 years, respectively; a 38-year-old cousin (son of a mother’s brother; III-18) was affected by cognitive impairment since the age of 10, and developed hallucinations, social isolation, and aggressive mood at the age of 18, being diagnosed as paranoid schizophrenia (ICD-10); and a 28-year-old cousin (daughter of a mother’s brother; III-28) was affected by epilepsy since the age of 3. The mother of the probands developed a colorectal adenocarcinoma (TNM: pT3 N1b) when she was 51 years old.
Patient’s data have been submitted to the ClinVar database with accession number SCV001147007. The study was conducted in accordance with the Declaration of Helsinki and national guidelines. Written informed consent was obtained from the patients’ guardian for the publication of this study and any potentially identifying images.