Abstract
Joubert syndrome (OMIM #213300) is a rare neurodevelopmental disease characterized by abnormal breathing patterns, intellectual impairment, ocular findings, renal cysts, and hepatic fibrosis. It is classified as a ciliopathy disease, where cilia function or structure in various organs are affected. Here, we report a 17-year-old male whose main clinical findings are oculomotor apraxia and truncal ataxia. Magnetic resonance imaging revealed the characteristic molar tooth sign of Joubert syndrome. He also has obsessive–compulsive disorder concomitantly, which is not a known feature of Joubert syndrome. Molecular genetic analysis revealed a homozygous c.2106G>A (p.(Thr702=)) variation in the Abelson helper integration 1 (AHI1) gene and another homozygous c.1739C>T (p.Thr580Ile) variation in the coiled-coil and C2 domain-containing protein 1A (CC2D1A) gene. Even though certain AHI1 variations were previously associated with Joubert syndrome (JS), c.2106G>A (p.(Thr702=)) was only reported in one patient in trans with another known pathogenic JS variant. The CC2D1A c.1739C>T (p.Thr580Ile) variation, on the other hand, has been reported to cause autosomal recessive nonsyndromic mental retardation, but there are conflicting interpretations about its pathogenicity. Overall, to our knowledge, this is the first patient representing a severe ciliopathy phenotype caused by a homozygous synonymous AHI1 variation. Further investigations should be performed to determine any involvement of the CC2D1A gene in ciliopathy phenotypes such as Joubert syndrome.
Highlights
IntroductionJoubert syndrome (JS) can affect many body parts, but it is primarily a disorder of brain development
We present a patient carrying homozygous variations in Abelson helper integration 1 (AHI1) (NM_001134831.2) and coil and C2 domaincontaining protein 1A (CC2D1A) (NM_017721.5) genes, who was diagnosed with Joubert syndrome (JS) coexistent with obsessive–compulsive disorder
The patient had delayed motor and cognitive milestones in his past medical history. His mother described symptoms consistent with neonatal episodic hyperpnea and hypotonia for the early childhood period. He had inability to initiate voluntary saccades in a head-fixed position, while saccades can be initiated by the vestibulo-ocular reflex, which is suggestive of oculomotor apraxia (Video S1) and truncal ataxia (Video S1)
Summary
JS can affect many body parts, but it is primarily a disorder of brain development. It is characterized by a malformed brain stem (molar tooth appearance), which normally controls breathing and swallowing reflexes. Absence or underdevelopment of the cerebellar vermis that regulates balance and coordination is observed in JS. As these regions are affected, patients suffer from ataxia, oculomotor apraxia, abnormal breathing patterns (hyperpnea), and sleep apnea starting from early childhood. Muscular hypotonia, intellectual disability, retinal dystrophy, polydactyly, and renal disease are common symptoms that can be associated with JS in patients
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