Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis).

OBJECTIVE: To identify genetic causes of COACH syndrome BACKGROUND: COACH syndrome is a rare autosomal recessive disorder characterised by Cerebellar vermis hypoplasia, Oligophrenia (developmental delay/mental retardation), Ataxia, Coloboma, and Hepatic fibrosis. The vermis hypoplasia falls in a spectrum of mid-hindbrain malformation called the molar tooth sign (MTS), making COACH a Joubert syndrome related disorder (JSRD). METHODS: In a cohort of 251 families with JSRD, 26 subjects in 23 families met criteria for COACH syndrome, defined as JSRD plus clinically apparent liver disease. Diagnostic criteria for JSRD were clinical findings (intellectual impairment, hypotonia, ataxia) plus supportive brain imaging findings (MTS or cerebellar vermis hypoplasia). MKS3/TMEM67 was sequenced in all subjects for whom DNA was available. In COACH subjects without MKS3 mutations, CC2D2A, RPGRIP1L and CEP290 were also sequenced. RESULTS: 19/23 families (83%) with COACH syndrome carried MKS3 mutations, compared to 2/209 (1%) with JSRD but no liver disease. Two other families with COACH carried CC2D2A mutations, one family carried RPGRIP1L mutations, and one lacked mutations in MKS3, CC2D2A, RPGRIP1L and CEP290. Liver biopsies from three subjects, each with mutations in one of the three genes, revealed changes within the congenital hepatic fibrosis/ductal plate malformation spectrum. In JSRD with and without liver disease, MKS3 mutations account for 21/232 families (9%). CONCLUSIONS: Mutations in MKS3 are responsible for the majority of COACH syndrome, with minor contributions from CC2D2A and RPGRIP1L; therefore, MKS3 should be the first gene tested in patients with JSRD plus liver disease and/or coloboma, followed by CC2D2A and RPGRIP1L.

Role of positron emission tomography in determining the extent of CNS ischemia in patients with sickle cell disease.

Nearly 25% of patients with sickle cell disease (SCD) experience central nervous system morbidity involving both large and small vessel disease. Optimal imaging methods for determining the extent of ischemia are not known. Positron emission tomography (PET) has the unique ability to show tissue function as well as structure. Reports concerning patients with non-SCD neurodegenerative disorders suggest PET may be useful in determining prognosis. We compared magnetic resonance imaging, magnetic resonance angiography, and neuropsychological testing with PET prospectively. Six patients with SCD and a history of stroke, aged 10 to 28, were enrolled. PET studies were performed on an ECAT HR 47 scanner (Siemens/CTI, Knoxville, TN) using 18-F-fluorodeoxyglucose as a tracer. PET interpretations were conducted in blinded fashion. MRI studies found two patients with only small vessel disease and four with both large and small vessel disease. In two of four subjects with large vessel disease, PET showed a corresponding metabolic abnormality and also identified an area of hypometabolism extending beyond the anatomical lesion as shown by MRI. PET did not demonstrate an abnormality corresponding with small vessel disease. Detailed neuropsychological testing demonstrated cognitive dysfunction in all cases. For some patients, PET may add sensitivity in detecting impaired metabolism in the area surrounding a major vessel infarct. However, the technique does not appear to be generally useful in characterizing small watershed or deep white matter infarcts. Larger studies, to include control subjects and carefully selected untransfused SCD patients, are needed. A combination of conventional imaging and neuropsychological testing remains the preferred evaluation for most SCD patients with neurologic symptoms.

Unusual dyskinesia complicating cardiopulmonary bypass surgery.

Four infants developed dyskinesia after cardiopulmonary bypass surgery three to four days postoperatively. The dyskinesia was choreoathetotic, and involved mainly the mouth, tongue and face. It was absent during sleep. Three of these infants improved over periods of several weeks, but one infant remained dyskinetic one year postoperatively. Neuro-imaging studies and EEGs were of little value in determining the cause of the dyskinesia. The factors responsible for the involuntary movements and for their severity remain unexplained.

Encephalitis lethargica-like illness in a girl with mycoplasma infection.

We describe a patient with mycoplasma infection and clinical manifestations of encephalitis lethargica. The patient was brought to our attention after acute neurologic deterioration followed by a prolonged sleep-like state and the emergence of extrapyramidal features. MRI of the brain disclosed a striking pattern of subcortical involvement by the inflammatory process, corroborating the clinical picture.

Rett syndrome. A commonly overlooked progressive encephalopathy in girls.

We report 15 cases of Rett syndrome, a slowly progressive disorder that occurs only in girls and is characterized by early deterioration of higher brain function with dementia and autistic behavior, loss of purposeful use of the hands, and deceleration of head growth. Epilepsy, with minor motor seizures being the predominant type, has its onset between 2 and 4 years of age in the majority of cases. Additional features include an extrapyramidal disorder with dystonia and choreoathetosis, and lactic acidemia. A precise biochemical marker of this disorder has not been identified.