aggressive behavior

Microcephaly 20, Primary, Autosomal Recessive

Clinical Characteristics

Ocular Features:

Microphthalmia and optic nerve hypoplasia with "blindness" seem to be common.

Systemic Features:

Short stature and global developmental delay are usually present. Poor or absent speech is characteristic and intellectual disability may be severe. Few individuals can walk. Foot deformities and hypotonia are often present. Behavior problems are common having features of ADHD, autism, and aggression. Foot deformities have been noted.

Imaging of the brain may reveal cerebellar hypoplasia, a simplified gyral pattern, and absence of the corpus callosum.

Genetics

Homozygous or compound heterozygous mutations in the KIF14 gene (1q32.1) are responsible for this disorder.

Pedigree:

Autosomal recessive

Treatment

Treatment Options:

No treatment has been reported.

References

Article Title:

Biallelic variants in KIF14 cause intellectual disability with microcephaly

Makrythanasis P, Maroofian R, Stray-Pedersen A, Musaev D, Zaki MS, Mahmoud IG, Selim L, Elbadawy A, Jhangiani SN, Coban Akdemir ZH, Gambin T, Sorte HS, Heiberg A, McEvoy-Venneri J, James KN, Stanley V, Belandres D, Guipponi M, Santoni FA, Ahangari N, Tara F, Doosti M, Iwaszkiewicz J, Zoete V, Backe PH, Hamamy H, Gleeson JG, Lupski JR, Karimiani EG, Antonarakis SE. Biallelic variants in KIF14 cause intellectual disability with microcephaly. Eur J Hum Genet. 2018 Mar;26(3):330-339.

PubMed ID:

29343805

Mutations of KIF14 cause primary microcephaly by impairing cytokinesis

Moawia A, Shaheen R, Rasool S, Waseem SS, Ewida N, Budde B, Kawalia A, Motameny S, Khan K, Fatima A, Jameel M, Ullah F, Akram T, Ali Z, Abdullah U, Irshad S, Hohne W, Noegel AA, Al-Owain M, Hortnagel K, Stobe P, Baig SM, Nurnberg P, Alkuraya FS, Hahn A, Hussain MS. Mutations of KIF14 cause primary microcephaly by impairing cytokinesis. Ann Neurol. 2017 Oct;82(4):562-577.

PubMed ID:

28892560

Neurodevelopmental Disorder, Mitochondrial, with Abnormal Movements and Lactic Acidosis

Clinical Characteristics

Ocular Features:

Optic atrophy is sometimes present. Nystagmus, and strabismus are seen in some patients. A pigmentary retinopathy was found in one individual.

Systemic Features:

This is a clinically heterogeneous disorder with extensive neurological deficits. Patients have feeding and swallowing difficulties from the neonatal period. There is intrauterine growth retardation and postnatally patients usually exhibit psychomotor delays and intellectual disabilities. Some develop seizures and few achieve normal developmental milestones. Axial hypotonia is present from early infancy and most patients have muscle weakness and atrophy. However, there may be spastic quadriplegia which is often associated with dysmetria, tremor, and athetosis. Ataxia eventually develops in most patients.

Brain imaging shows cerebral and cerebellar atrophy, enlarged ventricles, white matter defects, and delayed myelination.

Incomplete metabolic studies suggest there may be abnormalities in mitochondrial oxidative phosphorylation activity in at least some tissues. Most patients have an elevated serum lactate.

Death in childhood is common.

Genetics

Homozygous and compound heterozygous mutations in the WARS2 gene have been found in several families with this condition. The considerable variation in the phenotype may at least partially be explained by the fact that an additional variant in the W13G gene is sometimes present which impairs normal localization of the WARS2 gene product within mitochondria.

The transmission pattern in several families is consistent with autosomal recessive inheritance.

Pedigree:

Autosomal recessive

Treatment

Treatment Options:

No treatment has been reported for the general condition.

References

Article Title:

Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA synthase in six individuals with mitochondrial encephalopathy

Wortmann SB, Timal S, Venselaar H, Wintjes LT, Kopajtich R, Feichtinger RG, Onnekink C, Muhlmeister M, Brandt U, Smeitink JA, Veltman JA, Sperl W, Lefeber D, Pruijn G, Stojanovic V, Freisinger P, V Spronsen F, Derks TG, Veenstra-Knol HE, Mayr JA, Rotig A, Tarnopolsky M, Prokisch H, Rodenburg RJ. Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA synthase in six individuals with mitochondrial encephalopathy. Hum Mutat. 2017 Dec;38(12):1786-1795.

PubMed ID:

28905505

Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated in the etiology of autosomal recessive intellectual disability

Musante L, Puttmann L, Kahrizi K, Garshasbi M, Hu H, Stehr H, Lipkowitz B, Otto S, Jensen LR, Tzschach A, Jamali P, Wienker T, Najmabadi H, Ropers HH, Kuss AW. Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated in the etiology of autosomal recessive intellectual disability. Hum Mutat. 2017 Jun;38(6):621-636.

PubMed ID:

28236339

Deficiency of WARS2, encoding mitochondrial tryptophanyl tRNA synthetase, causes severe infantile onset leukoencephalopathy

Theisen BE, Rumyantseva A, Cohen JS, Alcaraz WA, Shinde DN, Tang S, Srivastava S, Pevsner J, Trifunovic A, Fatemi A. Deficiency of WARS2, encoding mitochondrial tryptophanyl tRNA synthetase, causes severe infantile onset leukoencephalopathy. Am J Med Genet A. 2017 Sep;173(9):2505-2510.

PubMed ID:

28650581

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