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.