Neurological and Developmental Features
• Global developmental delay: Present in all affected individuals; delays in gross motor milestones (e.g., sitting, walking) and speech.
• Intellectual disability: Ranges from moderate to severe.
• Hypotonia: Generalized, often noted in infancy and early childhood.
• Autistic features: Poor eye contact, weak social interaction, stereotypic behaviors.
• Seizures: Myoclonic seizures reported in some cases; EEG abnormalities include bilateral sharp waves and diffuse dysfunction.
• Motor dysfunction: Wide-based gait, ankle pronation, delayed independent ambulation.
• Speech delay: Many individuals remain non-verbal or have limited expressive language.
Facial Dysmorphism: There is no recognizable facial gestalt, however common features include prominent philtrum, everted lower lip, tented/open mouth, ptosis, hypo- or hypertelorism, synophrys or thick eyebrows, micrognathia or prognathism, depressed nasal bridge and strabismus.
Hepatic and Gastrointestinal Features
• Hypercholanemia: Elevated serum bile acids in most tested individuals.
• Intractable pruritus: Often progressive and severe.
• Hepatomegaly: Detected via imaging in several cases.
• Gallstones: Present in multiple individuals; some required endoscopic intervention.
• Steatorrhea and chronic diarrhea
• Feeding difficulties: Including need for nasogastric support in infancy.
• Gastroesophageal reflux
• Constipation
• Fat malabsorption: Suggested by clinical features and zebrafish model data.
Growth and Anthropometry
• Failure to thrive: Low weight and height percentiles in many cases.
• Progressive microcephaly: Documented in several individuals with longitudinal data.
• Macrocephaly: Observed in one proband (Family 9), suggesting phenotypic variability.
Neuroimaging and EEG
• MRI findings: Mild ventriculomegaly, delayed myelination, benign enlargement of subarachnoid spaces.
• EEG: Diffuse neuronal dysfunction without epileptiform discharges in some cases.
WDR83OS