Microcephaly, primary autosomal recessive

Qu'est-ce que la microcéphalie, autosomique récessive primaire ?

Also often referred to as MPCH it is a rare genetic syndrome that presents with a very small head and a very small brain. There are around 200 families currently recorded as diagnosed with the syndrome. The syndrome has a much higher prevalence in some regions of the world, specifically North Pakistan.

This syndrome is also known as:
MCPH1; MCPH2; MCPH3; MCPH5; MCPH6; MCPH7

Quels changements génétiques causent la microcéphalie, autosomique primaire récessive ?

Environ 50 % de tous les cas de syndrome sont causées par des mutations du gène ASPM. le syndrome est hérité selon un mode autosomique récessif.

L'hérédité autosomique récessive signifie qu'un individu affecté reçoit une copie d'un gène muté de chacun de ses parents, lui donnant deux copies d'un gène muté. Les parents porteurs d'une seule copie de la mutation du gène ne présenteront généralement aucune symptômes, mais ont 25 % de chances de transmettre les copies des mutations génétiques à chacun de leurs enfants.

Quels sont les principaux symptômes de la microcéphalie, autosomique récessive primaire ?

A very small head and a very small brain are defining features of the syndrome. However this smallness of the brain does not generally lead to any issues concerning the structure of the brain.

However intellectual disability is a symptom of the syndrome. The disability may be mild to moderate. This often leads to delayed speech and language development as well. Motor skill development tends to be only slightly delayed.

There does not tend to be any other main symptoms connected with or caused by the syndrome. In some cases symptoms might include mild seizures, behavior and attention issues or a shorter stature than other family members.

Possible clinical traits/features:
Global developmental delay, Proptosis, Microcephaly, Autosomal recessive inheritance, Sensorineural hearing impairment, Sloping forehead, Intellectual disability, moderate, Simplified gyral pattern, Small cerebral cortex

Comment est-ce que quelqu'un se fait tester pour la microcéphalie, récessive autosomique primaire ?

Les premiers tests de Microcephaly, primary autosomal recessive peut commencer par un dépistage par analyse faciale, en passant par le FDNA Telehealth plateforme de télégénétique, qui permet d'identifier les marqueurs clés de la syndrome et souligner la nécessité de tests supplémentaires. Une consultation avec un conseiller génétique puis un généticien suivra. 

Sur la base de cette consultation clinique avec un généticien, les différentes options pour les tests génétiques seront partagées et le consentement sera recherché pour des tests supplémentaires.

Informations médicales sur Microcephaly, primary autosomal recessive

There is a form of microcephaly called 'true' autosomal recessive microcephaly. Affected individuals have a very small vault to the skull but the face is of normal size. The ears appear large and the forehead is sloping. Motor milestones are initially normal and seizures or other neurological abnormalities are not a major part of the condition (a squint is often absent - see Phadke et al., 1993). After the first year of life, speech is delayed and the children tend to fall behind with their development. The diagnosis is made from the characteristic clinical features in the absence of any environmental causes for microcephaly. Further supporting evidence would be a CAT scan that did not show major structural abnormalities of the brain. Individual gyri might be relatively broad and the convolutional pattern of the hemispheres simplified ( McCreary et al., 1996).
Opitz and Holt (1990) provide an exhaustive review of microcephaly syndromes. Jackson et al., (1998) mapped the gene to 8p22 in two consanguineous Pakistani Asian families. Roberts et al., (1999) mapped a second locus (MCPH2) to 19q13.1-19q13.2. A third locus (MCPH3) was mapped by Moynihan et al., (2000) to 9q34. A fourth locus MCPH4) was mapped to 15q by Jamieson et al. (1999) - see under microcephaly - autosomal recessive - CASC5 mutations. A fifth locus (MCPH5) was mapped to 1q31 by Jamieson et al., (2000) and Pattison et al., (2000). MCPH4 has been mapped to 15q21.1 and mutations found in CEP152 (Guernsey et al., 2010).
Jackson et al., (2002) identified mutations in a gene coding for a BRCA1 C-terminal domain-containing protein (designated microcephalin) in MCPH1 families mapping to 8q23. A missense mutation creating a premature stop codon was found in 2 consanguineous Pakistani families. This seemed to be on the same ancestral haplotype of 9 microsatellite markers.
Roberts et al., (2002) studied 56 consanguineous families from Pakistan and found that families mapping to MCPH5 were the most prevalent, followed by MCPH2, MCPH1 and MCPH3. None mapped to MCPH4. Gul et al., (2006) looked at 33 Pakistani families. Eighteen mapped to MCPH5, 2 to MCPH2, 2 to MCPH4 and 1 to MCPH6.
Bond et al., (2002) demonstrated mutations in the ASPM gene in MCPH5. This is the human ortholog of the Drosophila melanogaster abnormal spindle gene (ASP) which is essential for normal mitotic spindle function in embryonic neuroblasts. This suggests that 'brain size is controlled in part through modulation of mitotic spindle activity in neuronal progenitor cells'. A further 3 MCPH5 families and 1 MCPH2 family were reported by Kumar et al., (2004). This was out of a total of 9 Indian families. The family reported by Shen et al., (2005) with ASPM mutations, had members with intractable seizures. Prenatal diagnosis in two families reported by Tunca et al., (2006) was achieved by a combination of DNA linkage and morphometry.
Leal et al., (2003) mapped a locus (MCPH6) in a consanguineous Brazilian family to 13q12.2. The phenotype was just moderate to severe intellectual impairment without neurological problems and with normal motor skills. The gene at MCPH6 has now been identified (Bond et al., 2005) and is a centromere-associated protein J (CENPJ). The same group also found the gene at MCPH3 which is, cyclin-dependent kinase 5 regulatory associated protein 2 (CDK5RAP2). A Pakistani family with a mutation in this gene was reported by Hassan et al., (2007). A CENPJ mutation in a Pakistani family was reported by Gul et al., (2006). A further 6 ASPM (MCPH5) mutations in consanguineous Pakistani families were reported by Gul et al., (2007).
Basel-Vanagaite et al., (2003 and 2006), have mapped a non-syndromic autosomal recessive condition to 19p13, and found mutations in CC2D1A, a putative signal transducer.
A new location (1p32), a new gene (STIL) in 3 Indian families were reported by Kumar et al., (2009).
MCPH2, located at 19q13 has now been found to have mutations in WDR62 - encoding a spindle pole protein (Nicholas et al., 2010, Yu et al., 2010). Three MCPH2 families were studied by Bhat et al., (2011) and mutations were found in WDR62. Of interest is that some of these patients had pachygyria, microlissencephaly, band heterotopias, and dysplastic cortices. A duplication of WDR62 also causes the condition (Rupp et al., 2014).
Banerjee et al. (2016) reported a 5-year-old Chinese girl with biallelic missense mutations in the WDR62 gene. The patient had markedly reduced brain size and intellectual disability. The girl only had scant hair on the top of the head. Seizures had not been observed. The patient was hypotonic and had scoliosis. She had wide and depressed nasal bridge, thick lips, hypertelorism, sloping forehead, high palate, and low-set and large ears. Brain imaging showed a slight enlargement of lateral brain ventricles and enlargement of the fourth ventricle; thinning of the corpus callosum with the absence of the splenium; dysplasia of the temporal lobe with small hippocampus, enlarged temporal horn and broadening lateral fissure; leukodystrophy, dysplasia of the white matter; suspected schizencephaly in the right parietal lobe and slight atrophy of the brainstem and cerebellum. The patient had unusual blisters and reticular hyperpigmentation and hypopigmentation on the trunk. Her nails and mucous membranes appeared normal. Histological examination of skin biopsy revealed acanthosis, hyperkeratosis and necrotic keratinocytes. There was melanin in melanophages in the upper dermis.

* This information is courtesy of the L M D.
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