MKS1 regulates ciliary INPP5E levels in Joubert syndrome.

BACKGROUND: Joubert syndrome (JS) is a recessive ciliopathy characterised by a distinctive brain malformation 'the molar tooth sign'. Mutations in >27 genes cause JS, and mutations in 12 of these genes also cause Meckel-Gruber syndrome (MKS). The goals of this work are to describe the clinical features of MKS1-related JS and determine whether disease causing MKS1 mutations affect cellular phenotypes such as cilium number, length and protein content as potential mechanisms underlying JS. METHODS: We measured cilium number, length and protein content (ARL13B and INPP5E) by immunofluorescence in fibroblasts from individuals with MKS1-related JS and in a three-dimensional (3D) spheroid rescue assay to test the effects of disease-related MKS1 mutations. RESULTS: We report MKS1 mutations (eight of them previously unreported) in nine individuals with JS. A minority of the individuals with MKS1-related JS have MKS features. In contrast to the truncating mutations associated with MKS, all of the individuals with MKS1-related JS carry ≥ 1 non-truncating mutation. Fibroblasts from individuals with MKS1-related JS make normal or fewer cilia than control fibroblasts, their cilia are more variable in length than controls, and show decreased ciliary ARL13B and INPP5E. Additionally, MKS1 mutant alleles have similar effects in 3D spheroids. CONCLUSIONS: MKS1 functions in the transition zone at the base of the cilium to regulate ciliary INPP5E content, through an ARL13B-dependent mechanism. Mutations in INPP5E also cause JS, so our findings in patient fibroblasts support the notion that loss of INPP5E function, due to either mutation or mislocalisation, is a key mechanism underlying JS, downstream of MKS1 and ARL13B.

Congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome: a rare cause of parainfectious rhabdomyolysis.

Congenital cataracts-facial dysmorphism-neuropathy syndrome (CCFDN, MIM: 604168), is a recently delineated neurogenetic disease causing recurrent episodes of rhabdomyolysis; prevention and early diagnosis of rhabdomyolysis should be part of the clinical management of the disease.

Acute necrotizing encephalopathy of childhood in non-Asian patients: report of three cases and literature review.

Acute necrotizing encephalopathy of childhood is a novel type of parainfectious encephalopathy with a racial and geographic predilection, rarely reported from other than East Asian areas. The objective was to describe the clinical, imaging, and other laboratory findings of non-Asian patients with acute necrotizing encephalopathy. Data were collected from three patients diagnosed in Athens over a 4-year period plus 16 cases reported from other European and North American countries. One of the Greek children died, and the other two had a normal outcome. A neuropathologic examination in the fatal case showed edematous necrosis without inflammatory, reactive, or proliferative changes. Data from Greek and other non-Asian patients support the homogeneity of the disease worldwide.

Acute necrotizing encephalopathy associated with parainfluenza virus in a Caucasian child.

Acute necrotizing encephalopathy is a severe parainfectious disorder with a clear racial predilection for Oriental children living in the Far East. The prognosis was originally reported as grave; however, a mild form of the disease has recently been described. A case of parainfluenza virus-associated acute necrotizing encephalopathy in a Caucasian child with a mild clinical course and excellent prognosis is presented. In this patient, the initial clinical picture was not very impressive, and the diagnosis was delayed until the third week of the illness, when neuroimaging was performed. Two months later, clinical and neuroimaging findings had almost completely resolved. Suggested criteria for a benign prognosis, such as normal liver function and cerebrospinal fluid protein levels, asymmetric thalamic lesions, and no brainstem involvement, were relevant in the present case. An extended diagnostic work-up for metabolic, vascular, coagulation, and infectious diseases was negative apart from a seroconversion for parainfluenza virus. To our knowledge, this is the first reported case of acute necrotizing encephalopathy associated with parainfluenza virus infection. Acute necrotizing encephalopathy, especially in the mild form, might not be fully recognized and could be underdiagnosed in Europe, where the reported incidence of the syndrome is very low.

Split-cord malformation in a girl with Angelman syndrome: a mere coincidence?

We present a case of a girl with both Angelman syndrome and split-cord malformation. The child was initially referred at the age of 2.5 years, for developmental delay and a possible diagnosis of spina bifida occulta, based on the presence of a hair tuft located on the midline of the lumbar area. Magnetic resonance imaging of the spine showed split-cord malformation below L1, whereas a cytogenetically detected deletion of chromosome bands 15q11-q13 (SNRPN) confirmed the clinical diagnosis of Angelman syndrome. Split-cord malformation or diastematomyelia is a rare form of spina bifida occulta that occurs sporadically and is not particularly related to specific syndromes. Hair patches or other distinctive cutaneous stigmata such as those seen in the present case have not, to our knowledge, been reported in other patients with Angelman syndrome; therefore, the association of Angelman syndrome and split-cord malformation in this child is probably coincidental. Spinal cord abnormalities have not been consistently reported in patients with Angelman syndrome; only one adult patient with Angelman syndrome and spina bifida occulta has been reported, and this association was probably considered fortuitous. However, some relatively uncommon clinical features such as deterioration of gait, lower limb malformations, and bladder dysfunction, particularly as the patients age, although nonspecific, are reminiscent of such a cause. We therefore urge clinicians to look for cutaneous stigmata along the spine and consider the evaluation of the spinal cord in children with apparent paraparesis, out of proportion to that usually seen in Angelman syndrome, should our case report not just be a coincidental observation.