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Pallister-Killian syndrome is a rare, multi-system developmental diagnosis typically caused by tetrasomy of chromosome 12p that exhibits tissue-limited mosaicism. The spectrum of clinical manifestations in Pallister-Killian syndrome is wide and includes craniofacial anomalies, clefts, ophthalmologic, audiologic, cardiac, musculoskeletal, diaphragmatic, gastrointestinal, genitourinary, and cutaneous anomalies in association with intellectual disability and seizures. Growth parameters are often normal to elevated at birth with deceleration of growth postnatally. No formal estimate of the prevalence of Pallister-Killian syndrome has been made. Here, we report the clinical findings in 59 individuals with Pallister-Killian syndrome who were ascertained at Pallister-Killian syndrome Foundation family meetings held in the summers of 2006, 2008, 2009, and 2010. In addition, the clinical findings of 152 cases reported in the medical literature were reviewed and compared to the cohort examined here. Several novel clinical characteristics were identified through detailed dysmorphology examinations of this cohort and reassertion of a mild developmental variant is described. This report expands the clinical manifestations of Pallister-Killian syndrome and highlights the variable expressivity of this diagnosis with important implications for diagnosis and counseling.

Lysosomal storage disorders (LSDs) are considered to be a rare metabolic disease for the national health forum, clinicians, and scientists. This study aimed to know the prevalence of different LSDs, their geographical variation, and burden on the society. It included 1,110 children from January 2002 to December 2012, having coarse facial features, hepatomegaly or hepatosplenomegaly, skeletal dysplasia, neuroregression, leukodystrophy, developmental delay, cerebral-cerebellar atrophy, and abnormal ophthalmic findings. All subjects were screened for I-cell disease, glycolipid storage disorders (NiemannPick disease A/B, Gaucher), and mucopolysaccharide disorders followed by confirmatory lysosomal enzymes study from leucocytes and/or fibroblasts. Niemann-Pick disease-C (NPC) was confirmed by fibroblasts study using filipin stain. Various storage disorders were detected in 387 children (34.8 %) with highest prevalence of glycolipid storage disorders in 48 %, followed by mucopolysaccharide disorders in 22 % and defective sulfatide degradation in 14 % of the children. Less common defects were glycogen degradation defect and protein degradation defect in 5 % each, lysosomal trafficking protein defect in 4 %, and transport defect in 3 % of the patients. This study demonstrates higher incidence of Gaucher disease (16 %) followed by GM2 gangliosidosis that includes Tay-Sachs disease (10 %) and Sandhoff disease (7.8 %) and mucopolysaccharide disorders among all LSDs. Nearly 30 % of the affected children were born to consanguineous parents and this was higher (72 %) in children with Batten disease. Our study also demonstrates two common mutations c.1277_1278insTATC in 14.28 % (4/28) and c.964G>T (p.D322Y) in 10.7 % (3/28) for Tay-Sachs disease in addition to the earlier reported c.1385A>T (p.E462V) mutation in 21.42 % (6/28).

The neuronal ceroid lipofuscinoses (NCLs) are the most common group of neurodegenerative diseases in children. Mutations in the CLN1 gene, which encodes the enzyme palmitoyl protein thioesterase 1 (PPT1), usually cause infantile-onset NCL (INCL) (Santavouri-Haltia disease, MIM 256730). 1 INCL has an age at onset of 8 to 18 months with rapid visual and psychomotor deterioration, ataxia, hypotonia, and seizures. 2 Retinal pigment aggregation does not usually occur. In all cases, a granular pattern of storage material in cells is observed by electron microscopy. However, in one family, onset was as late as adulthood. 3 We describe a second family with adult-onset NCL caused by a novel mutation in the CLN1/PPT1 gene.Case report. A 24-year-old woman with no significant family history was diagnosed with hypomanic episodes because of a 12-to 24-month history of "low self-esteem and mood, irritability, lack of interest, and bizarre behavior including a tendency to wander the streets" and thus treated with olanzapine and valproate. A few months later, she reported the inability to see properly. Ophthalmologic evaluation showed normal visual acuity, pupillary reaction, and normal optic discs and macular and retinal appearance in the presence of "extremely tubular" tunnel vision in both eyes when the automated visual field tests were performed but with inconsistent responses on Goldman's fields assessment. She had a history of declining academic abilities after age 18 years. She was emotionally labile, but no other neurologic abnormalities were detected.Brain MRI showed marked generalized cerebral and cerebellar atrophy with no focal abnormalities (figure) (see also figure E-1 on the Neurology Web site at www.neurology.org). Hematologic, biochemical, and vasculitic screens and standard lysosomal enzymes assays were normal. Visual evoked responses were delayed bilaterally. Flash electroretinograms were nondetectable (extinguished). Attenuated pattern electroretinograms (P50 and N95) were found. The EEG showed excess of slow activity with superimposed runs of medium voltage sharp and wave activity throughout the recording. Neuropsychological assessment revealed substantial dysfunction in intellectual ability, memory, language skills, visual processing, and executive functioning.Nearly 18 months after her presentation and with further but slow cognitive decline, she started to experience vivid and sometimes terrifying visual hallucinations. These included seeing huge snakes, elephants, and sometimes people. The introduction of risperidone did not resolve these symptoms. At 19 months' follow-up, a repeat MRI showed minor progression in the degree of brain atrophy. A repeat retinal examination then showed few but typical areas of retinitis pigmentosa (figure). There has been no evidence of seizures, myoclonic jerks, or other involuntary movements. Rectal and skin biopsy samples and blood were examined comprehensively by light microscopic techniques, and subsequently ultrastructural analysis was done by transmission electron mic...

Sanfilippo syndrome type B (mucopolysaccharidosis IIIB) is an autosomal recessive disease that is caused by the deficiency of the lysosomal enzyme alpha-N-acetylglucosaminidase (NAGLU). NAGLU is involved in the degradation of the glycosaminoglycan (GAG) heparan sulphate, and a deficiency results in the accumulation of partially degraded GAGs inside lysosomes. Early clinical symptoms include hyperactivity, aggressiveness and delayed development, followed by progressive mental deterioration, although there are a small number of late-onset attenuated cases. The gene for NAGLU has been fully characterized and we report the molecular analysis of 18 Sanfilippo B families. In total, 34 of the 36 mutant alleles were characterized in this study and 20 different mutations were identified including 8 novel changes (R38W, V77G, 407-410del4, 703delT, A246P, Y335C, 1487delT, E639X). The four novel missense mutations were transiently expressed in Chinese hamster ovary cells and all were shown to decrease the NAGLU activity markedly, although A246P did produce 12.7% residual enzyme activity.