Miller-Dieker Lissencephaly syndrome

Was ist Miller-Dieker Lissencephaly syndrome?

It is a rare genetic syndrome. The main condition of the syndrome is lissencephaly, abnormal brain development that leads to the development of a brain without the normal folds and grooves. Instead the brain is smooth. This in turn causes many of the main symptoms of the syndrome. The severity of the syndrome depends on how smooth the brain is.

This syndrome is also known as:
Lissencephaly - type I Lissencephaly syndrome MDLS Mds Myotonia - cold induced Myotoniacoldinduced Periodic paralysis - paramyotonia congenita Periodicparalysisparamyotoniacongenita Potassium-aggrevated myotonia Potassiumaggrevatedmyotonia Sodium channel myotonia Sodiumchannelmyotonia

Was Genveränderungen verursachen Miller-Dieker Lissencephaly syndrome?

Das Syndromes wird durch eine Deletion von genetischem Material am oder in der Nähe des kurzen Arms des Chromosoms 17 p13 verursacht. 3. Die Größe dieser Löschung variiert zwischen Personen, und die Größe der Löschung kann erklären, warum einige betroffene Personen schwerwiegendere Symptome haben als andere.

Das Syndrom kann in einem autosomal dominanten Muster vererbt werden, aber die meisten Fälle sind das Ergebnis von De-novo oder neuen Deletionen, die während der Reproduktion auftreten.

Im Falle einer autosomal dominanten Vererbung ist nur ein Elternteil der Träger der Genmutation, und sie haben eine 50% ige Chance, sie an jedes ihrer Kinder weiterzugeben. Syndrome, die in einer autosomal dominanten Vererbung vererbt werden, werden durch nur eine Kopie der Genmutation verursacht.

In einigen Fällen kann ein genetisches Syndrom das Ergebnis einer De-novo-Mutation und der erste Fall in einer Familie sein. In diesem Fall handelt es sich um eine neue Genmutation, die während des Fortpflanzungsprozesses auftritt.

Was sind die wichtigsten symptome von Miller-Dieker Lissencephaly syndrome?

Lissencephaly is the main symptom of the syndrome.That affects the cerebral cortex of the exterior surface of the brain. The abnormal development caused by the syndrome leads to a brain with less folds and grooves than usual and a smoother brain as a result.

This abnormal brain development triggers further symptoms. These include severe intellectual disability and developmental delay. Seizures, muscle stiffness, low muscle tone and issues with feeding are amongst these symptoms.

Unique facial features of the syndrome include a prominent forehead, a sunken middle of the face, a small nose, low set and abnormally shaped ears, a small jaw and a thick upper lip. In some individuals slower growth is recorded.

Possible clinical traits/features:
Abnormality of metabolism/homeostasis, Abnormality of the cardiovascular system, Cavum septum pellucidum, Cataract, Wide nasal bridge, Cerebral cortical atrophy, Polyhydramnios, Cleft palate, Aplasia/Hypoplasia of the corpus callosum, Short nose, Anteverted nares, Nephropathy, Lissencephaly, Low-set ears, Midline brain calcifications, Micrognathia, Intellectual disability, Intrauterine growth retardation, Inguinal hernia, Infantile muscular hypotonia, Joint contracture of the hand, High forehead, Gray matter heterotopia, Hypoplasia of the corpus callosum, Incoordination, Failure to thrive, Delayed eruption of teeth, Motor delay, Deep palmar crease, Duodenal atresia, Epicanthus, EEG abnormality, Decreased fetal movement, Cryptorchidism, Clinodactyly of the 5th finger, Malformation of the heart and great vessels, Contiguous gene syndrome, Thick upper lip vermilion, Thin upper lip vermilion, Microcephaly, Infantile spasms, Recurrent aspiration pneumonia, Camptodactyly, Progressive spastic paraplegia

Wie wird jemand getestet? Miller-Dieker Lissencephaly syndrome?

The initial testing for Miller-Dieker Lissencephaly syndromet 5 can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.

Medizinische Informationen zu Miller-Dieker Lissencephaly syndrome

Miller-Dieker Lissencephaly syndrome(MLDS) is a syndrome caused by a microdeletion on 17p13.3. Haploinsufficiency of PAFAH1B1, formerly the LIS1 gene, appears to cause lissencephaly (see LISSENCEPHALY1; LIS1) while loss of downstream genes in this region lead to additional features associated with MLDS. These features include a prominent forehead, bitemporal narrowing, a depressed nasal bridge, anteverted nares, midface hypoplasia and a prominent upper lip with a thin vermilion border.
Infants with type I lissencephaly (Dobyns et al., 1985) may be divided into those without significant dysmorphic features (isolated lissencephaly sequence, ILS) and those with dysmorphic features (Miller-Dieker syndrome). In the latter there is postnatal growth deficiency and a characteristic facial appearance. Microcephaly is common, but not invariable, and is usually not severe in the neonatal period. Characteristic facial features include a prominent forehead, bitemporal narrowing, a depressed nasal bridge, anteverted nares, midface hypoplasia and a prominent upper lip with a thin vermilion border (Allanson et al., 1998). Vertical furrowing of the forehead is present only in about 25% of cases and is usually present only in the neonatal period. There is frequently prolonged neonatal jaundice. CT and MRI scans show severe lissencephaly and, characteristically, a midline focus of calcification in the callosal remnant (this is seen in about 40% of patients with Miller-Dieker syndrome but is not usually seen in isolated lissencephaly sequence). Neuropathological investigation has revealed a 4-layer cortex (Viot et al., 2004). Other associated malformations include congenital heart defect (in cases with a large chromosome deletion) and post-axial polydactyly. Chitayat et al., (1997) reported a case with an omphalocele, and Ueda et al., (2006) a case with a gallbladder cancer.
About 50-70% of cases with Miller-Dieker syndrome can be shown to have a deletion of 17p13.3 by light microscopy and almost all the remainder will have a submicroscopic deletion, most easily demonstrated by fluorescent in situ hybridisation (FISH) (Kuwano et al., 1991; Dobyns et al., 1993). Ledbetter (1992) mentions a case with a cryptic telomeric translocation, present in one parent, and only demonstrable by FISH. A further maternal cryptic translocation was reported by Masuno et al., (1995). Honda et al., (1998) reported a case with a balanced 8p11.23;17p13.3 translocation. Joyce et al., (2002) reported a family where there were numerous miscarriages and a case of Miller-Dieker syndrome secondary to an 11p;17p translocation. Pollin et al., (1999) present data for recurrence risks where a parent carries a translocation involving 17p13.3.
Reiner et al., (1993) demonstrated mutations in a gene from the beta-transducin family of G protein-like molecules (LIS-1). Hattori et al., (1994) showed that LIS-1 was in fact a subunit of brain platelet-activating factor. Chong et al., (1997) and Lo Nigro et al., (1997) carried out further studies on LIS1 and demonstrated point mutations and deletions of the LIS1 gene in patients with isolated lissencephaly and Miller-Dieker syndrome. They suggest that mutations within the LIS1 gene cause isolated lissencephaly and that facial dysmorphism associated with Miller-Dieker syndrome may be caused by haploinsufficiency for genes distal to LIS1.
Isolated lissencephaly (ie: without dysmorphic features) is heterogeneous. About 20-30% of cases have submicroscopic deletions of 17p using the commercial L132 probe and about 40% are deleted for the LIS1 gene (Dobyns et al., 1993). Pilz et al., (1998) also found that using a LIS1 probe detected about 40% of deletions in cases of isolated lissencephaly. Intrauterine CMV infection and early placental insufficiency may be other causes. After exclusion of cases with known aetiology, Dobyns et al., (1992) found that 3 out of 41 sibs were affected, a recurrence risk of about 7%.
Pilz et al., (1998) studied patients with isolated lissencephaly, looking for mutations of the LIS1 or XLIS gene and estimated that mutations in these genes accounted for approximately 75% of cases. In patients with LIS1 mutations, brain malformations were more severe over the parietal and occipital regions, whereas in patients with XLIS mutations the abnormalities were more severe over the frontal cortex (Dobyns et al., 1999). Sakamoto et al., (1998) studied 12 patients with isolated lissencephaly or MIller-Dieker syndrome and found deletions of part of the LIS1 gene in 6, and 1-bp deletion of the LIS1 gene in one other case. Pilz et al., (1999) found the appearance of subcortical band heterotopia in two boys with missense mutations of the XLIS gene. They also found a missense mutation in the LIS1 gene in another boy with band heterotopia. In the study of 15 patients with classical lissencephaly and subcortical band heterotopia, Torres et al., (2004) found that of the 8 patients with LIS1 mutations, all had a milder phenotype (grades 4 to 6) with, in some, posterior agyria and anterior pachygyria.Cardoso et al., (2000) report phenotype/genotype correlations in patients with LIS1 mutations. Leventer et al., (2001) reported five patients with missense mutations in LIS1. They pointed out that the phenotype could be milder and reported a case with normal intelligence. Further deletions and mutations were reported by Cardoso et al., (2002).
Partial pachygyria, either bilateral frontal or bilateral posterior, with superimposed polymicrogyria may be autosomal recessive in a significant proportion of cases. Dobyns and Truwit (1995) provide a good review of syndromes featuring lissencephaly. Barkovich et al., (1996) presented a comprehensive classification for malformation of cortical development.
Fox and Walsh (1999) and Barkovich et al., (2001) provide good reviews of the genetics of neuronal migration defects. Kuzniecky and Barkovich (2001) and Kato and Dobyns provide good reviews of abnormalities of cortical development.
Ross et al., (2001) provided a classification of the group of conditions characterised by lissencephaly with cerebellar hypoplasia (LCH). Group LCHa is characterised by lissencephaly with mild cerebellar vermis hypoplasia. One child with a LIS1 mutation was found with this brain scan appearance.
Toyo-oka et al., (2003) showed that the gene encoding 14-3-3epsilon (YWHAE), one of a family of ubiquitous phosphoserine/threonine-binding proteins, is always deleted in individuals with MDS. Mice deficient in Ywhae have defects in brain development and neuronal migration, similar to defects observed in mice heterozygous with respect to Pafah1b1. Mice heterozygous with respect to both genes have more severe migration defects than single heterozygotes.
Fong et al., (2004), suggest that delayed cortical development might be seen on 23 week prenatal ultrasound scans, and that when seen should lead to further investigation.
Mei et al., (2008) looked at 45 patients with isolated lissencephaly. LIS1 mutations were found in 44% and 1 had a duplication. They suggest that MLPA has a high yield and should be the method of choice for molecular diagnosis.
Bellucco et al. (2017) described a 6-month-old male patient with Miller-Dieker syndrome. The patient’s mother had a history of ectopic pregnancies and a first trimester spontaneous abortion. The patient had dysmorphic features, including microcephaly, oblique palpebral fissures, hypertelorism, upturned nares, long philtrum, thin superior lip, micrognathia, low-set ears, transverse palmar creases, and bilateral cryptorchidism. He also had recurrent seizures and developmental delay. Renal ultrasound showed multicystic dysplastic left kidney, echocardiogram showed patent foramen ovale. Brain MRI revealed lissencephaly and bilateral absence of auditory evoked potential. The authors found an unbalanced t(17;Y), that resulted in a 5.5-Mb 17p deletion, and a karyotype with 45 chromosomes. The deletion region encompassed 167 genes, including 91 OMIM genes.

* This information is courtesy of the L M D.
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