A number sign (#) is used with this entry because pontocerebellar hypoplasia type 1B (PCH1B) is caused by homozygous or compound heterozygous mutation in the EXOSC3 gene (606489) on chromosome 9p13. Description Pontocerebellar hypoplasia type 1B is a severe autosomal recessive neurologic disorder characterized by a combination of cerebellar and spinal motor neuron degeneration beginning at birth. There is diffuse muscle weakness, progressive microcephaly, global developmental delay, and brainstem involvement (summary by Wan et al., 2012). PCH1B can be divided into mild, moderate, and severe subgroups that vary in age at onset, progression, clinical and neuroradiologic severity, and survival (summary by Halevy et al., 2014). For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1A (607596).

A number sign (#) is used with this entry because of evidence that pontocerebellar hypoplasia type 1A (PCH1A) is caused by homozygous mutation in the VRK1 gene (602168) on chromosome 14q32. Description Pontocerebellar hypoplasia (PCH) refers to a group of severe neurodegenerative disorders affecting growth and function of the brainstem and cerebellum, resulting in little or no development. Different types were classified based on the clinical picture and the spectrum of pathologic changes. PCH type 1 is characterized by central and peripheral motor dysfunction associated with anterior horn cell degeneration resembling infantile spinal muscular atrophy (SMA; see SMA1, 253300); death usually occurs early. Genetic Heterogeneity of Pontocerebellar Hypoplasia Also see PCH1B (614678), caused by mutation in the EXOSC3 gene (606489); PCH1C (616081), caused by mutation in the EXOSC8 gene (606019); PCH1D (618065), caused by mutation in the EXOSC9 gene (606180); PCH2A (277470), caused by mutation in the TSEN54 gene (608755); PCH2B (612389), caused by mutation in the TSEN2 gene (608753); PCH2C (612390), caused by mutation in the TSEN34 gene (608754); PCH2D (613811), caused by mutation in the SEPSECS gene (613009); PCH3 (608027), caused by mutation in the PCLO gene (604918); PCH4 (225753), caused by mutation in the TSEN54 gene; PCH5 (610204), caused by mutation in the TSEN54 gene; PCH6 (611523), caused by mutation in the RARS2 gene (611524); PCH7 (614969), caused by mutation in the TOE1 gene (613931); PCH8 (614961), caused by mutation in the CHMP1A gene (164010); PCH9 (615809), caused by mutation in the AMPD2 gene (102771); PCH10 (615803), caused by mutation in the CLP1 gene (608757); PCH11 (617695), caused by mutation in the TBC1D23 gene (617687); and PCH12 (618266), caused by mutation in the COASY gene (609855).

A severe, genetic form of pontocerebellar hypoplasia (PCH) characterized by spinal cord anterior horn cell degeneration in addition to pontocerebellar hypoplasia. Clinically, patients manifest with a severe global development deficit that is evident early on from difficulties in feeding and swallowing Epidemiology About 115 patients with pontocerebellar hypoplasia type 1 (PCH1) have been reported. Clinical description The clinical course is severe. Neonates with PCH1 present with hypotonia, impaired swallowing with subsequent feeding difficulties, and progressive, postnatal microcephaly. A severe psychomotor deficit subsequently becomes apparent. If patients survive past infancy, patients have oculomotor manifestations including strabismus, nystagmus, occulomotor apraxia. The most severe cases of PCH1 manifest prenatally with polyhydramnios and arthrogryposis multiplex congenital.

Pontocerebellar hypoplasia type 1 (PCH1) is a genetic disease that affects the development of the brain. Babies and children with this disease have an unusually small and underdeveloped cerebellum , which is the part of the brain that coordinates movement. A region of the brain called the pons also fails to develop properly. The pons, which is located at the base of the brain in an area called the brainstem , sends signals between the cerebellum and the rest of the brain. Individuals with PCH1 also experience a degeneration of the anterior horn cells , which are responsible for helping the spinal cord send signals to the muscles.

Due to the limited number of reported cases, insufficient research has been conducted on musicogenic seizures and musicogenic epilepsy. [1] It has been suggested that the disorder has a higher tendency to affect females, while the average age of onset is 28. [9] Nonetheless, the age of presentation is usually at 39, therefore suggesting an underestimated prevalence. [4] Moreover, the underestimated prevalence of musicogenic seizures could also be due to challenges in diagnosis such as deducing music as a seizure trigger. [4] References [ edit ] ^ a b c d e f g h i j k l Ellis, Liddy (2017-03-01).

Spondyloepimetaphyseal dysplasia, aggrecan type is a new form of skeletal dysplasia characterized by severe short stature, facial dysmorphism and characteristic radiographic findings. Epidemiology To date, three cases have been described, all originating from the same family. Clinical description Facial features include midface hypoplasia with almost absent nasal cartilage, and relative prognathism and macrocephaly. Radiographic findings include irregular epiphyses of long bones with widened metaphyses, platyspondyly, multiple cervical-vertebral clefts and brachydactyly. Etiology The disease results from a missense mutation affecting the C-type lectin domain of aggrecan ( AGC1 gene; chromosome 15) which regulates endochondral ossification.

Williams syndrome is a genetic condition that affects many parts of the body. Signs and symptoms include mild to moderate intellectual disability; unique personality traits; distinctive facial features; and heart and blood vessel problems. Williams syndrome is caused by a person missing more than 25 genes from a specific area of chromosome 7 (a "deletion"). The loss of these genes contributes to the characteristic features. Although Williams syndrome is an autosomal dominant condition, most cases are not inherited and occur sporadically in people with no family history of Williams syndrome. Treatments are based on each person's signs and symptoms, as there is no cure at this time.

Summary Clinical characteristics. Williams syndrome (WS) is characterized by cardiovascular disease (elastin arteriopathy, peripheral pulmonary stenosis, supravalvar aortic stenosis, hypertension), distinctive facies, connective tissue abnormalities, intellectual disability (usually mild), a specific cognitive profile, unique personality characteristics, growth abnormalities, and endocrine abnormalities (hypercalcemia, hypercalciuria, hypothyroidism, and early puberty). Feeding difficulties often lead to poor weight gain in infancy. Hypotonia and hyperextensible joints can result in delayed attainment of motor milestones. Diagnosis/testing. Clinical diagnostic criteria are available for Williams syndrome; however, the diagnosis requires detection of a recurrent 7q11.23 contiguous gene deletion of the Williams-Beuren syndrome critical region (WBSCR) that encompasses the elastin gene ( ELN ). This contiguous gene deletion can be detected using fluorescent in situ hybridization (FISH) and/or deletion/duplication testing. Management. Treatment of manifestations: Early intervention programs, special education programs, and vocational training address developmental disabilities; programs include speech/language, physical, occupational, feeding, and sensory integration therapies.

Williams syndrome Other names Williams–Beuren syndrome (WBS) Two men, age 21 and 28, displaying several of the facial features characteristic of Williams syndrome. [1] Specialty Medical genetics , pediatrics Symptoms Facial changes including underdeveloped chin structure, intellectual disability, overly friendly nature, short height [2] Complications Heart problems , periods of high blood calcium [2] [3] Duration Lifelong [2] Causes Genetic [2] Differential diagnosis Noonan syndrome , fetal alcohol syndrome , DiGeorge syndrome [2] Treatment Various types of therapy [2] Prognosis Shorter life expectancy [4] Frequency 1 in 7,500 to 1 in 20,000 [5] Williams syndrome ( WS ) is a genetic disorder that affects many parts of the body. [3] Facial features frequently include a broad forehead, underdeveloped chin, short nose and full cheeks. [3] While mild to moderate intellectual disability with particular problems with visual spatial tasks such as drawing is typical, verbal skills are generally relatively unaffected. [3] Those affected often have an outgoing personality , interact readily with strangers, and appear happy. [3] [5] Problems with teeth, heart problems (especially supravalvular aortic stenosis ), and periods of high blood calcium are common. [2] [3] Williams syndrome is caused by a genetic abnormality, specifically a deletion of about 27 genes from the long arm of one of the two chromosome 7s . [3] [5] Typically this occurs as a random event during the formation of the egg or sperm from which a person develops. [3] In a small number of cases, it is inherited from an affected parent in an autosomal dominant manner. [3] The different characteristic features have been linked to the loss of specific genes . [3] The diagnosis is typically suspected based on symptoms and confirmed by genetic testing . [2] Treatment includes special education programs and various types of therapy . [2] Surgery may be done to correct heart problems. [2] Dietary changes or medications may be required for high blood calcium. [2] The syndrome was first described in 1961 by New Zealander John C. ... These delays continue into childhood, where patients with Williams syndrome are delayed in learning to walk. [24] In young children, the observed motor delay is around five to six months, though some research suggests that children with Williams syndrome have a delay in development that becomes more extreme with age. [28] Children with motor delays as a result of Williams syndrome are particularly behind in the development of coordination, fine motor skills such as writing and drawing, response time, and strength and dexterity of the arms. ... Journal of Child Psychology and Psychiatry . 28 (2): 297–309. doi : 10.1111/j.1469-7610.1987.tb00212.x .

A rare genetic multisystemic neurodevelopmental disorder characterized by a distinct facial appearance, cardiac anomalies (most frequently supravalvular aortic stenosis), cognitive and developmental abnormalities, and connective tissue abnormalities (such as joint laxity).

Description Williams-Beuren syndrome is a multisystem disorder caused by hemizygous deletion of 1.5 to 1.8 Mb on chromosome 7q11.23, which contains approximately 28 genes. Pober (2010) reviewed the clinical features of Williams-Beuren syndrome as well as the genomic and genetic basis and clinical management.

Familial thoracic aortic aneurysm and aortic dissection (Familial TAAD) is a rare condition that affects the aorta (the large blood vessel that distributes blood from the heart to the rest of the body). In people affected by this condition, the thoracic aorta (the upper part of the aorta, near the heart) may become weakened, stretched and/or enlarged. This can lead to a sudden tear of the inner wall of the aorta that allows blood to flow between the aorta's inner and outer walls (also called a dissection). These aortic abnormalities can be life-threatening as they can decrease blood flow to other parts of the body and/or cause the aorta to rupture. The onset of the condition varies significantly from person to person, even within the same family.

Annuloaortic ectasia Other names Cystic medial necrosis of aorta [1] Specialty Cardiology, vascular surgeon Annuloaortic ectasia is a dilation of the proximal ascending aorta and aortic annulus . It may cause aortic regurgitation , thoracic aortic dissection , aneurysm and rupture. It is often associated with connective tissue diseases like Marfan syndrome and Ehlers Danlos Syndrome . [2] It can also be a complication due to tertiary syphilis . In tertiary syphilis the aortic root becomes so dilated that the aortic valve becomes incompetent and cor bovinum results. The term was first coined by the American heart surgeon Denton Cooley in 1961. [3] References [ edit ] ^ RESERVED, INSERM US14-- ALL RIGHTS.

A number sign (#) is used with this entry because of evidence that progressive familial intrahepatic cholestasis-3 (PFIC3) is caused by mutation in the gene encoding the class III multidrug resistance (MDR3) P-glycoprotein (ABCB4; 171060). For a general phenotypic description and a discussion of genetic heterogeneity of PFIC, see PFIC1 (211600). Clinical Features De Vree et al. (1998) reported 2 unrelated patients with PFIC3. The first patient was a Turkish boy, born of consanguineous parents, who had recurrent bouts of jaundice from the age of 3 months, when he presented with severe icterus, diarrhea, fever, and pruritus. At the age of 3 years, he showed hepatosplenomegaly, elevated serum liver enzymes, increased gamma-glutamyltransferase (GGT1; 612346) activity (6 times normal), and a high serum bile acid concentration (50 times normal).

Progressive familial intrahepatic cholestasis (PFIC) refers to a heterogeneous group of autosomal recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin. Epidemiology The exact prevalence remains unknown, but the estimated prevalence at birth varies between 1/50,000 and 1/100,000. Clinical description Three types of PFIC have been identified and are related to mutations in hepatocellular transport system genes involved in bile formation. PFIC1 and PFIC2 (see these terms) usually appear in the first months of life, whereas onset of PFIC3 (see this term) may also occur later in infancy, in childhood or even during young adulthood. Main clinical manifestations include cholestasis, pruritus and jaundice.

A number sign (#) is used with this entry because progressive familial intrahepatic cholestasis-4 (PFIC4) is caused by homozygous or compound heterozygous mutation in the TJP2 gene (607709) on chromosome 9q21. For a phenotypic description and a discussion of genetic heterogeneity of progressive familial intrahepatic cholestasis, see PFIC1 (211600). Clinical Features Sambrotta et al. (2014) reported 12 patients from 8 families with early childhood onset of severe progressive liver disease. One child died at age 13 months, 9 patients required a liver transplant, and 2 had stable liver disease with mild portal hypertension at ages 4 and 7 years, respectively. Laboratory studies showed normal or mildly increased GGT levels. No additional clinical details were given.

Jacquemin et al. (1994) concluded that Byler disease is caused by a defect in primary bile acid secretion. In liver biopsies from 28 patients with PFIC and low GGT1 levels, Alonso et al. (1994) found canalicular cholestasis and disruption of the liver cell plate.

Progressive familial intrahepatic cholestasis Other names PFIC [1] Specialty Internal medicine Progressive familial intrahepatic cholestasis (PFIC) is a group of familial cholestatic conditions caused by defects in biliary epithelial transporters. The clinical presentation usually occurs first in childhood with progressive cholestasis . This usually leads to failure to thrive , cirrhosis , and the need for liver transplantation . Contents 1 Types 2 Signs and symptoms 3 Pathogenesis 4 Diagnosis 5 Treatment 6 Prognosis 7 Epidemiology 8 See also 9 References 10 External links Types [ edit ] Types of progressive familial intrahepatic cholestasis are as follows: Type 1 (OMIM #211600), also called Byler disease Type 2 (OMIM #601847), also called ABCB11 deficiency or BSEP deficiency Type 3 (OMIM #602347), also called ABCB4 deficiency or MDR3 deficiency Type 4 (OMIM #615878), from mutation in TJP2 Signs and symptoms [ edit ] The onset of the disease is usually before age 2, but patients have been diagnosed with PFIC even into adolescence . Of the three entities, PFIC-1 usually presents earliest. Patients usually present in early childhood with cholestasis , jaundice , and failure to thrive .

3-hydroxyacyl-CoA dehydrogenase deficiency is an inherited condition that prevents the body from converting certain fats to energy, particularly during prolonged periods without food (fasting). Initial signs and symptoms of this disorder typically occur during infancy or early childhood and can include poor appetite, vomiting, diarrhea, and lack of energy (lethargy). Affected individuals can also have muscle weakness (hypotonia), liver problems, low blood sugar (hypoglycemia), and abnormally high levels of insulin (hyperinsulinism). Insulin controls the amount of sugar that moves from the blood into cells for conversion to energy. Individuals with 3-hydroxyacyl-CoA dehydrogenase deficiency are also at risk for complications such as seizures, life-threatening heart and breathing problems, coma, and sudden death.

3-hydroxyacyl-coenzyme A dehydrogenase deficiency Other names HADH deficiency 3-hydroxyacyl-coenzyme A dehydrogenase deficiency is a rare condition that prevents the body from converting certain fats to energy, particularly during fasting. [1] Normally, through a process called fatty acid oxidation , several enzymes work in a step-wise fashion to metabolize fats and convert them to energy. People with 3-hydroxyacyl-coenzyme A dehydrogenase deficiency have inadequate levels of an enzyme required for a step that metabolizes groups of fats called medium chain fatty acids and short chain fatty acids ; for this reason this disorder is sometimes called medium- and short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (M/SCHAD) deficiency. [ citation needed ] Contents 1 Signs and symptoms 2 Genetics 3 Diagnosis 4 Treatment 5 See also 6 References 7 External links Signs and symptoms [ edit ] Typically, initial signs and symptoms of this disorder occur during infancy or early childhood and can include poor appetite, vomiting, diarrhea, lethargy , hypoglycemia , hypotonia , liver problems, and hyperinsulinism (high levels of insulin). Insulin controls the amount of sugar that moves from the blood into cells for conversion to energy. Individuals with 3-hydroxyacyl-coenzyme A dehydrogenase deficiency are also at risk for complications such as seizures, life-threatening heart and breathing problems, coma, and sudden unexpected death. Problems related to 3-hydroxyacyl-coenzyme A dehydrogenase deficiency can be triggered by periods of fasting or by illnesses such as viral infections.

A number sign (#) is used with this entry because of evidence that 3-alpha-hydroxyacyl-CoA dehydrogenase deficiency is caused by compound heterozygous mutation in the HADH gene (601609) on chromosome 4q25. Clinical Features Tein et al. (1991) reported a 16-year-old girl with 3-hydroxyacyl-CoA dehydrogenase deficiency resulting in juvenile-onset recurrent myoglobinuria, hypoketotic hypoglycemic encephalopathy, and hypertrophic/dilated cardiomyopathy. Biochemical analysis showed that HADH enzyme activity was markedly decreased in skeletal muscle cells, whereas it was normal in fibroblasts. Bennett et al. (1999) reported 3 unrelated patients with HADH deficiency resulting in sudden infant death. Clinically, there were variable features of hypotonia, hypoglycemia, hepatic steatosis, and hypoketotic dicarboxylic aciduria.

Hyperinsulinism due to short chain 3 hydroxylacyl-CoA dehydrogenase (SCHAD) deficiency is a recently described mitochondrial fatty acid oxidation disorder characterized by hyperinsulinemic hypoglycemia with seizures, and in one case fulminant hepatic failure. Epidemiology Less than 10 cases have been reported to date. Clinical description The disease can present in infancy or early childhood. It presents with the manifestations of hyperinsulinemic hypoglycemia with vomiting, lethargy and seizures. Complications include coma and sudden death. It has responded well to diazoxide. Etiology It is caused by a mutation in the HADH gene (4q22-q26) encoding the SCHAD protein that has a dual function both as an enzyme and an inhibitor of glutamate dehydrogenase.

Genotype/Phenotype Correlations In a study of 97 patients with diabetes diagnosed in the first 6 months of life whose diabetes remitted before the age of 5 years, 64 of whom had previously been reported, Flanagan et al. (2007) found that 70 of 97 (72%) had an abnormality at the 6q24 locus: 27 (39%) had paternal uniparental isodisomy, 28 (40%) had a duplication of the paternal allele, and 15 (22%) had a methylation defect. Of the remaining 28 TNDM patients without 6q24 abnormalities, 13 were found to have a mutation in the ABCC8 gene (600509) and 12 in the KCNJ11 gene (600937); in 3 patients no mutation was found.

A number sign (#) is used with this entry because this form of transient neonatal diabetes mellitus is caused by mutation in the ABCC8 gene (600509). For a phenotypic description and a discussion of genetic heterogeneity of transient neonatal diabetes mellitus, see 601410. From a group of 73 patients with neonatal diabetes, Babenko et al. (2006) screened the ABCC8 gene in 34 who did not have alterations in chromosome 6q (see 601410) or mutations in the KCNJ11 (600937) or GCK (138079) genes. They identified heterozygosity for 5 different mutations (see, e.g., 600509.0019 and 600509.0020) in 7 patients with transient neonatal diabetes mellitus. They also identified heterozygosity for mutations (600509.0017 and 600509.0018) in 2 patients with permanent neonatal diabetes (606176).

Transient neonatal diabetes mellitus (TNDM) is a genetically heterogeneous form of neonatal diabetes (NDM, see this term) characterized by hyperglycemia presenting in the neonatal period that remits during infancy but recurs in later life in most patients. Epidemiology The prevalence of neonatal diabetes is estimated to be between 1/95,000 to 1/400,000 live births. About 50% of NDM cases are transient (TNDM) and 50% permanent (PNDM, see this term). The condition has been reported in all ethnic groups and affects male and female infants equally. Clinical description Cardinal clinical manifestations include severe intrauterine growth retardation, hyperglycemia (within the first week of life beginning in the neonatal period and resolving usually by 18 months of age), and dehydration.

Transient neonatal diabetes mellitus (TNDB) is a type of diabetes that appears within the first few weeks of life but is transient; affected infants go into remission within a few months, with possible relapse to permanent diabetes in adolescence or adulthood. Affected individuals have slow growth before birth followed by hyperglycemia , dehydration and failure to thrive in infancy. Approximately 70% of cases are caused by the overactivity of certain genes in a region of the long (q) arm of chromosome 6 called 6q24. These cases are referred to as 6q24-related TNDB ; most (but not all) of these cases are not inherited. Other genetic causes include mutations in the KCNJ11 and ABCC8 genes, which usually cause permanent neonatal diabetes .

6q24-related transient neonatal diabetes mellitus is a type of diabetes that occurs in infants. This form of diabetes is characterized by high blood sugar levels (hyperglycemia) resulting from a shortage of the hormone insulin . Insulin controls how much glucose (a type of sugar) is passed from the blood into cells for conversion to energy. People with 6q24-related transient neonatal diabetes mellitus experience very slow growth before birth (severe intrauterine growth retardation). Affected infants have hyperglycemia and an excessive loss of fluids (dehydration), usually beginning in the first week of life.

Transient neonatal diabetes Transient neonatal diabetes mellitus is inherited in an autosomal dominant manner [1] Specialty Pediatrics Transient neonatal diabetes mellitus ( TNDM ) is a form of neonatal diabetes presenting at birth that is not permanent. This disease is considered to be a type of maturity onset diabetes of the young (MODY). Contents 1 Types 2 Cause 3 Diagnosis 4 Management 5 See also 6 References 7 Further reading 8 External links Types [ edit ] Type OMIM Gene Locus Description TNDM1 601410 ZFP57 , PLAGL1 6p22.1, 6q24.2 TNDM2 610374 ABCC8 11p15.1 Due to the mutations of the other subunit of the K ATP channel, SUR1, which is encoded by the ABCC8 gene. [2] TNDM3 610582 KCNJ11 11p15.1 Cause [ edit ] This condition has to do with genetics and is often associated with having an added Chromosome 7 gene (mostly from the paternal side). [ citation needed ] The form on chromosome 6 can involve imprinting . [3] [4] Diagnosis [ edit ] This section is empty. You can help by adding to it . ( September 2017 ) Management [ edit ] This section is empty. You can help by adding to it . ( September 2017 ) See also [ edit ] Permanent neonatal diabetes mellitus References [ edit ] ^ "OMIM Entry - # 610582 - DIABETES MELLITUS, TRANSIENT NEONATAL, 3" . omim.org .