Clinical Quiz Answer
Clinical Quiz Answer
What is the diagnosis ?
In view of developmental regression, stereotypic midline hand movement, loss of speech, Rett syndrome (RTT) was suspected. Methyl-CpG-binding protein 2 (MECP2) gene was tested that showed a denovo heterozygous missense pathogenic variant c.401C>G. This variant has been reported in the literature to be associated with Rett syndrome, therefore the diagnosis of Rett syndrome in this girl was substantiated.
What is Rett syndrome?
Rett syndrome is a progressive neurodevelopmental disorder characterised by apparently normal psychomotor development during the first 6 to 18 months of life, followed by a rapid regression in language and motor skills. During the phase of rapid regression, replacement of purposeful hand use by repetitive, stereotypic hand movements is pathognomonic.
What are the clinical features of MECP2-related disorder?
MECP2-related disorders in females include classic Rett syndrome, variant Rett syndrome, and mild learning disabilities. It is typically lethal in males but rare surviving males can presented with neonatal encephalopathy and intellectual disability.
Classical Rett syndrome
There is usually apparently normal in psychomotor development during the first 6 to 18 months of life, followed by a rapid regression in language and motor skills. The hallmark is loss of purposeful hand use and replaced by repetitive stereotypical hand movements. Head growth may begin decelerating as early as age three months. Seizure occur in about 90% of females, mostly with generalised tonic-clonic seizures and partial complex seizures.1 They may have screaming fits and inconsolable crying by age 18-24 months. Additional characteristics include autistic features, panic-like attacks, bruxism, episodic apnoea and/or hyperpnoea, seizures, gait ataxia and apraxia, and tremors. After rapid deterioration, the neurologic manifestations become relatively stable. Other features including failure to thrive, maybe partially related to oropharyngeal and gastroesophageal incoordination resulting in poor dietary intake.2 Constipation is also very common in Rett syndrome. More than 80% of patients have scoliosis.3 About 70% of patients also have osteopenia and increases the risk of fractures.4 One of the most life threatening problem in Rett syndrome is cardiac arrhythmia that included prolonged QT interval, T-wave abnormalities, and reduced heart rate variability which may account for some cases of sudden death in Rett syndrome.5
Atypical RTT / Rett syndrome variant 6
- Preserved Speech Variant (Zappella Variant): developmental regression at 1-3 years old , with milder reduction of hand skills. There is recovery of language after regression at about mean age of 5 years old. This variant got a lower frequency of epilepsy, and relatively normal head circumference. Mutations in MECP2 were found in majority of cases.
- Early Seizure Variant (Hanefeld Variant): early onset of seizure, mostly before 5 months of life. MECP2 mutation is rarely found in this type of variant, instead CDKL5 mutation maybe found.
- Congenital Variant (Rolando Variant): Grossly abnormal initial development, with severe psychomotor delay and inability to walk. Microcephaly and regression occur much earlier than in classical Rett syndrome, with mostly in the first 4-5 months old. This variant is associated with FOXG1 mutations.
What are the diagnostic criteria of Rett syndrome?
The diagnostic criteria was updated and modified in 2010,6 which shown in table below: