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Arginine-glycine amidinotransferase (GATM) deficiency is an autosomal-recessive disorder caused by pathogenic variants in GATM. Clinical features include intellectual disability, hypotonia, and myopathy. Due to normal neurodevelopment in asymptomatic individuals on creatine monotherapy, GATM deficiency is a good candidate for newborn screening. To determine the carrier frequency of GATM deficiency, we performed functional characterization of rare missense variants in GATM reported as heterozygous in the Exome Variant Server database. To assess phenotype and genotype correlation, we developed a clinical severity scoring system. Two patients with mild phenotype had a nonsense missense variant. Severe phenotype was present in patients with missense as well as truncating variants. There seems to be no phenotype and genotype correlation. We cloned a novel GATM transcript. We found seven missense variants retaining 0% of wild-type GATM activity indicating putative pathogenicity. Based on our study results, high Genomic Evolutionary Rate Profiling conservation score, conserved amino acid substitution in species, and low allele frequency in exome databases would be the most sensitive in silico analysis tools to predict pathogenicity of missense variants. We present first study of the functional characterization of missense variants in GATM as well as clinical severity score of patients with GATM deficiency., (© 2016 WILEY PERIODICALS, INC.)

Background: The purpose of the study was to identify and molecularly characterize a neurological syndrome in a consanguineous Pakistani family., Methods: Five patients, their 2 siblings, and their parents were clinically examined. DNA from all 7 siblings was genotyped with Affymetrix SNP arrays and sequencing of selected candidate genes., Results: An unusual neurological syndrome of crawling gait, predominant leg dystonia, pyramidal signs, microcephaly, and suspected deafness segregated in the family. Three patients ambulated on hands and knees, either by hopping and crossing their legs, or by dragging the legs behind them. Two patients have acquired the ability to walk bipedally with a dystonic gait. Unexpectedly, no chromosomal region was homozygous in patients only. Under different disease models, we localized 7 chromosomal regions in the genome common to all patients. No pathogenic mutations were identified in selected candidate genes or the mitochondrial genome., Conclusion: We describe an unusual movement disorder syndrome reminiscent of but distinct from Uner Tan syndrome., (Copyright © 2011 Movement Disorder Society.)

Mental retardation affects 2-3% of the population and shows a high heritability.Neurodevelopmental disorders that include pronounced impairment in language and speech skills occur less frequently. For most cases, the molecular basis of mental retardation with or without speech and language disorder is unknown due to the heterogeneity of underlying genetic factors.We have used molecular karyotyping on 1523 patients with mental retardation to detect copy number variations (CNVs) including deletions or duplications. These studies revealed three heterozygous overlapping deletions solely affecting the forkhead box P1 (FOXP1) gene. All three patients had moderate mental retardation and significant language and speech deficits. Since our results are consistent with a de novo occurrence of these deletions, we considered them as causal although we detected a single large deletion including FOXP1 and additional genes in 4104 ancestrally matched controls. These findings are of interest with regard to the structural and functional relationship between FOXP1 and FOXP2. Mutations in FOXP2 have been previously related to monogenic cases of developmental verbal dyspraxia. Both FOXP1 and FOXP2 are expressed in songbird and human brain regions that are important for the developmental processes that culminate in speech and language., (©2010 Wiley-Liss, Inc.)

Deficiency of enzyme acid beta-galactosidase causes GM1 gangliosidosis. Patients with adult GM1 gangliosidosis typically present with generalized dystonia. We describe clinical, bone marrow, and radiological features of adult GM1 gangliosidosis to help improve its recognition. We report 3 Indian patients and review of reports between 1981 and October 2002. The disease frequently is reported in the Japanese literature (75%). Patients are normal at birth and have normal early motor and mental development. Onset is within the first decade with abnormal gait, or worsening of speech is an initial symptom. Dystonia occurs in 97% of patients. Facial dystonia described as "facial grimacing" observed in approximately 90% could be an important clinical clue. Dysarthria/anarthria (97%) is frequent, and eye movements are normal. Bone marrow examination may show Gaucher-like foam cells (39%). Magnetic resonance imaging (MRI) frequently (90.9%) shows bilateral symmetrical putamenal hyperintensities on T2-weighted and proton density images. Diagnosis is confirmed by demonstrating deficiency of beta-galactosidase. Adult (Type 3) GM1 Gangliosidosis commonly presents with generalized dystonia with prominent facial dystonia, severe speech disturbances, and normal eye movements. Bone marrow frequently shows Gaucher-like foam cells. MRI shows typical lesions in the putamen. Deficiency of beta-galactosidase in fibroblasts confirms the diagnosis.

Mutations in a number of forkhead transcription factors are associated with the development of inherited diseases in humans. Two closely related genes, FOXP2 and FOXP3, are implicated in two completely different human disorders. A point mutation in the forkhead domain of FOXP2 (R553H) is responsible for a severe speech and language disorder, while a series of missense mutations distributed over the forkhead domain of FOXP3 cause a fatal disorder called IPEX, characterized by immune dysregulation, polyendocrinopathy, and enteropathy. Homology model building techniques were used to generate atomic structures of FOXP2 and FOXP3, using the solution structures of the forkhead domain of the adipocyte-transcription factor FREAC-11 and AFX as templates. The impact of these disease-causing missense mutations on the three-dimensional structure, stability, and surface electrostatic charge distribution of the forkhead domains is examined here. The missense mutations R553H in FOXP2 and R397W in FOXP3 dramatically alter the electrostatic potentials of the molecular surface of their respective forkhead domains., (Copyright 2004 Wiley-Liss, Inc.)

Mutations in the MECP2 gene cause the severe neurodevelopmental disorder called Rett syndrome. Preliminary evidence suggests that MECP2 may be involved in a broader phenotype than classical Rett syndrome including preserved speech variants (PSV). Here we report clinical and mutation analysis of 18 PSV patients. Ten of them had a MECP2 mutation (55%). The clinical features of these girls have been characterized and two subgroups defined. All of them had slow recovery of verbal and praxic abilities, evident autistic behavior, and normal head circumference. Six were overweight, often obese, had kyphosis, coarse face, and mental age of two-to-three years, and were able to speak in sentences; four had normal weight, mental age not beyond one-to-two years, and spoke in single words and two-word phrases. The course of the disorder was in stages as in classic Rett syndrome. Hand-washing was present in the first years of life but often subsequently disappeared. Significantly, all mutations found in PSV are either missense or late truncating mutations. In particular, we did not find the four early truncating hot spots: R168X, R255X, R270X, R294X. These results suggest that early truncating mutations lead to a poor prognosis (classic Rett), while late truncating and missense mutations lead either to classic Rett or PSV. We hypothesize that a missense or late truncating mutation is necessary but not sufficient to produce a PSV, based on the presence of one (or more) modifier genes whose product may interact in a epistatic manner with MeCP2 protein., (Copyright 2001 Wiley-Liss, Inc.)

We report on a child with congenital heart disease (atrial septal defect, ventricular septal defect, pulmonic stenosis), submucosal cleft palate, hypernasal speech, learning difficulties, and right fifth finger anomaly manifestations, consistent with velocardiofacial syndrome (VCFS); however, cytogenetic analysis demonstrated a small terminal deletion of the segment 4q34.2 to 4qter. Fluorescent in situ hybridization did not identify a deletion of the critical region associated with VCFS. In previously reported 4q deletions with a breakpoint distal to 4q34.2, no cardiac defects or cleft of palate were reported. Our patient has a deletion of 4q34.2 to 4qter and has palate and cardiac involvement and minor learning difficulties, which implies that genes involved in heart and palate development lie distal to 4q34.2, and that the critical region for more severe mental retardation on 4q may reside proximal to 4q34.2. These results suggest that a distal 4q deletion can lead to a phenotype similar to VCFS and emphasizes the importance of searching for other karyotype abnormalities when a VCFS-like phenotype is present and a 22q deletion is not identified.

We report on two boys, monozygotic twins born to normal and nonconsanguineous parents, presenting with an unusual facial appearance, cortical atrophy, dolichocephaly, short stature, cleft palate, micrognathia, prominent upper central incisors, bilateral Sidney line, minor foot deformities, unstableness in walking, early hypotonia, hyperreflexia, hyperactivity, psychomotor retardation, and severe delay in language development. These manifestations resemble those previously described in the Smith-Fineman-Myers syndrome.

We report on a girl with Floating-Harbor syndrome, trigonocephaly due to metopic suture synostosis, preauricular pit, hypoplastic thumb, subluxated radial head, and Sprengel deformity. A review suggests that trigonocephaly may be an important craniofacial manifestation in this syndrome that is recognizable in infancy. With time, this finding appears to become less noticeable, and the face develops a triangular shape, accentuated by a broad and bulbous nose.

We describe two boys with global developmental delay and a phenotype of microcephaly, midface hypoplasia, enlarged fleshy ears, depressed nasal bridge, anteverted nostrils, central palatal ridge, and high forehead. Bilateral congenital fat pads are present anteromedial to the heels. Fetal finger and toe pads are present and palmar and plantar grooves are deeper than normal with "pillowing" of the areas between the grooves. No patients with similar clinical findings have been located, but these two children have a remarkably similar clinical presentation which we consider a "new" syndrome.

We describe three brothers from a non-consanguineous family with microcephaly, mental and physical retardation, speech disorder, facial anomalies, and internal hydrocephalus in two of the three affected brothers. The youngest brother died at the age of 5 months. He had situs abdominalis inversus, ASD II, and had been operated for internal hydrocephalus and atresia of the biliary duct. A search in the Oxford Medical Database Dysmorphology Program suggested phenotypic similarities with two sisters described in 1972 by Osvaldo Mutchinick in Argentina. Although differences in their phenotypes exist, it is possible that the two sets of sibs represent the same, rare syndrome. This interpretation is supported by the origin of both families from the same geographic region.

We report on a young male patient with an overgrowth syndrome, who had normal birth weight. He had a number of manifestations typical of the Weaver syndrome (WS), such as advanced bone age, peculiar craniofacial appearance, and camptodactyly. He also showed severe mental and speech retardation and demineralisation of the bones of the hands and feet. The latter can be considered as unreported manifestations of WS, or the patient could represent an example of a new WS-like syndrome.

We describe a family of 9 affected individuals in three generations with nocturnal oro-facio-brachial partial seizures, secondarily generalized partial seizures, and centro-temporal epileptiform discharges, associated with oral and speech dyspraxia and cognitive impairment. The speech disorder was prominent, but differed from that of Landau-Kleffner syndrome and of epilepsy with continuous spike and wave during slow-wave sleep. The electroclinical features of this new syndrome of autosomal dominant rolandic epilepsy resemble those of benign rolandic epilepsy, a common inherited epilepsy of childhood. This family shows clinical anticipation of the seizure disorder, the oral and speech dyspraxia, and cognitive dysfunction, suggesting that the genetic mechanism could be expansion of an unstable triplet repeat. Molecular studies on this syndrome, where the inheritance pattern is clear, could also be relevant to identifying a gene for benign rolandic epilepsy where anticipation does not occur and the mode of inheritance is uncertain.

Speech/language disorders are common in the fragile X syndrome. [Howard-Peebles, 1979: Am J Hom Genet 31:214-222; Renier et al., 1983: J Ment Defic Res 27:51-59; Sparks, 1984: Birth Defects and Speech-Language Disorders, pp. 39-43; Hanson et al., 1986: Am J Med Genet 23:195-206]. Verbal paraphasias have been considered a rare feature and word-finding difficulties have seldom been reported. Here we report on ten Brazilian patients who were evaluated for speech/language disturbances and found that word-finding difficulties were present in 50% of the cases, which is a slightly higher frequency than that of clear dyspraxia. We suggest, therefore, that word-finding difficulties and verbal dyspraxia can be a common feature within the spectrum of this syndrome. Additional speech findings are discussed.

The objective of this study was to determine the frequency of coprolalia in younger patients with Gilles de la Tourette syndrome (GTS). Coprolalia, which is the least understood and perhaps most unusual symptom of GTS, is reported to occur in 4-60% of all patients with GTS. Most reports indicate a prevalence > 30%. The widely varying prevalence figures for coprolalia may reflect cultural differences, severity of disease, and the age of the population surveyed. This study is a chart review of 112 patients seen in a pediatric neurology clinic in South Florida who met the Diagnostic and Statistical Manual of Mental Disorder (3rd ed., revised) criteria for GTS. Only 8% of the patients in the study exhibited coprolalia. This unusually low frequency of coprolalia suggests that coprolalia may be rarer than previously believed in younger patients. It may also better reflect the frequency of coprolalia in a community-based pediatric neurology practice.

Findings in a patient with mosaic isochromosome 8p are compared with those of previously reported cases. There were no distinguishing findings on physical examination; all had cognitive delays, especially in speech and language development.

A 13-item checklist that combines physical and behavioral traits typical of fragile X [fra(X)] syndrome was evaluated prospectively in the screening of 107 males with mental retardation or severe learning disabilities. The checklist was completed before we obtained cytogenetic results. Fifteen males were fra(X)-positive and the manifestations that differentiated fra(X)-positive and fra(X)-negative patients included perseverative speech, large or prominent ears, large testicles, and tactile defensiveness. The combination of physical and behavioral traits is helpful in suggesting the diagnosis and identifying high-risk patients. A total score of 16 or higher had a significant yield of fra(X)-positive patients (greater than or equal to 45%).

We studied the performance of 34 as yet undiagnosed individuals known to be at risk of Huntington disease (HD), on a maximum-effort oral-motor task. Results were compared with those from a normal control group matched for age and sex. The at-risk-of-HD population was significantly slower overall than the normal group on all 5 of the oral-motor tasks. This is interpreted as indicating that the presence of HD in the one half of the population expected to have it, affected the group's overall performance even though the clinical signs associated with HD had not yet appeared. In addition, rankings of repetition rates in both groups indicate that approximately one half of the at-risk population was consistently associated with the slowest 25% of the combined groups forming, in essence, a subgroup of the at-risk population. The performance of the other one half of the at-risk group did not differ systematically from that of the normal control persons. Minimal repetition rates were identified on each oral-motor task that may serve as early clinical "indicators" for the presence of HD in the population known to be at risk.

Clinical manifestations and other aspects of nonspecific X-linked mental retardation are reviewed using data from the literature and information on affected males in 24 new families ascertained in British Columbia. A great degree of variability was apparent in the mental abilities of affected males. Speech defects, other CNS disorders and minor physical changes such as "big" ears or a highly arched palate were not present in many cases. Evidence for the existence of a clinical entity of mental retardation associated with the fragile site at Xq27 or 28 and macro-orchidism is discussed. Genetic phenomena of reduced penetrance in males and of partial expression in females with respect of X-linked recessive genes are examined. Consideration is given to the question of whether this type of mental retardation is due to X-linked recessive or autosomal dominant sex-limited genes. Most ascertained cases of X-linked mental retardation are from families of northern European extraction. Recommendations are made regarding the diagnosis and counseling of X-linked mental retardation cases.

We report on two sibs with Angelman "happy puppet" syndrome. Out of 48 families reported in the literature, this is only the fourth family with affected sibs. A review of the literature shows a low but not negligible recurrence risk. Different explanations for this are discussed.

We report on 2 patients (3 1/2 year-old-male and 6-year-old female) with the ring 15 chromosome syndrome and speech delays and review 25 cases from the literature. The main characteristics of this syndrome include growth retardation (100%), variable mental retardation (95%), microcephaly (88%), hypertelorism (46%), and triangular facies (42%). Other frequent findings include delayed bone age (75%), brachydactyly (44%), speech delay (39%), frontal bossing (36%), anomalous ears (30%), café-au-lait spots (30%), cryptorchidism (30%), and cardiac abnormalities (30%). The average age at diagnosis was 8.1 years. The average maternal and paternal age at the time of birth was 28 and 31 years, respectively.

A proximal 15q deletion, del(15) (q11:q13), was detected in a child with Angelman syndrome by cytogenetic analysis of peripheral lymphocytes. The chromosomes of both parents appeared normal. Flow karyotype analysis carried out on lymphoblastoid cell lines derived from the child and her parents confirmed the presence of a de novo 15 deletion. The estimated size of the deleted segment ranged from 6.1-9.5% of chromosome 15 (approximately 6-9.3 million base pairs). The parental origin of the deleted chromosome could not be resolved by flow cytometry, but cytogenetic evidence suggested that it was derived from the smaller chromosome 15 homologue in the mother.

The language characteristics of fra(X) males (n = 10) with an IQ greater than or equal to 70 were evaluated. Language testing demonstrated relatively stronger receptive vocabulary skills compared to weak auditory memory and processing skills. A characteristic speech and language disturbance, cluttering, was present in 9 of the 10 study patients. Their speech was characterized by a fast and fluctuating rate of speech, and repetitions of sounds, words or phrases. Other aspects of cluttering including attentional problems, hyperactivity, motor delays and reading difficulties are commonly seen in the fra(X) syndrome. Cluttering may be helpful in identifying the fra(X) syndrome in a male who is not retarded.

We describe a boy with the manifestations of the SHORT syndrome: lipoatrophy, delayed speech development, minor facial anomalies, clinodactyly, and short stature. In addition, this boy had deafness, which was not previously reported in the SHORT syndrome.

We report on a 4-year-old girl with Angelman syndrome who has an apparent de-novo del(15) (q11q13) originating from a maternally derived chromosome. Her mother had severe brachycephaly, sensorineural hearing loss, speech impediment, and mild ataxia. CT brain scans showed an enlarged foramen magnum in the mother and daughter but magnetic resonance imaging (MRI) showed no brainstem abnormality in either. This family demonstrates that some Angelman syndrome cases may be dominantly transmitted with variable expression and associated with abnormal or cytogenetically apparently normal chromosome 15.

Duplication 18p was found in a 12-year-old girl whose father carried a balanced translocation involving the same chromosome segment, t(18;21)(p11;p11). Our patient had delayed speech development, mild psychomotor retardation, epilepsy, and minor anomalies, including a low nasal bridge, anti-mongolian eye slant, low-set ears, and narrowly arched palate. These findings are compared with eight previously published cases.