GeneReviews®

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GeneReviews®

Book. 1993

Authors: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A

Abstract
CLINICAL CHARACTERISTICS: KMT2B-related dystonia (DYT-KMT2B) is a complex childhood-onset (mean age 7 years) movement disorder described to date in 39 individuals. It is characterized by a progressive disease course evolving commonly from lower-limb focal dystonia into generalized dystonia with prominent cervical, cranial, and laryngeal involvement. Communication difficulties, secondary to articulation difficulties and low speech volume, are common. Bulbar dysfunction leads to impaired swallowing. Intellectual disability (ID) / developmental delay (DD) are commonly reported. Additional findings can include eye movement abnormalities, skin changes, psychiatric comorbidities (attention deficit hyperactivity disorder, anxiety, depression, and obsessive-compulsive disorder), myoclonus, seizures, spasticity, and sensorineural hearing loss. Many affected individuals follow a similar disease course, though milder and atypical findings have been described.
DIAGNOSIS/TESTING: The diagnosis of DYT-KMT2B is established in a proband with either a heterozygous pathogenic variant in KMT2B or a heterozygous interstitial deletion of 19q13.12 that includes a KMTB2 whole-gene deletion.
MANAGEMENT: Treatment of manifestations: Dystonia: Although pharmacologic treatment with levodopa and other commonly used anti-dystonic agents generally does not result in long-term benefit for the majority of patients, a trial of these agents is considered reasonable. One group observed a significant improvement of motor manifestations with an antimuscarinic (anticholinergic) agent. Bilateral globus pallidus interna deep brain stimulation results in substantial clinical improvement, particularly in younger patients. Other: Early initiation of physiotherapy and a tailored exercise program is advised as well as use of adaptive aids (e.g., ankle-foot orthoses, walkers) as necessary to support and maintain ambulation. Speech and language therapy is crucial to assist in feeding skills and communication. Nutrition specialists / dieticians are needed to assess calorie needs and reduce the risk of malnutrition. Address DD/ID issues through appropriate specialists/agencies. Surveillance: Regular monitoring of weight and height in children, nutritional status, swallowing function, speech and language, adaptive functioning (ability to perform activities of daily living), orthopedic complications (hip dislocation and kyphoscoliosis), hearing, eye movements, skin, and psychiatric status.
GENETIC COUNSELING: DYT-KMT2B is inherited in an autosomal dominant manner. To date, ~84% of individuals have the disorder as the result of a de novo KMT2B pathogenic variant and ~16% have inherited the KMT2B variant (10% from an affected parent; 6% from a clinically asymptomatic parent). Each child of an individual with DYT-KMT2B has a 50% chance of inheriting the KMT2B pathogenic variant; reduced penetrance and intrafamilial clinical variability have been reported. Once the KMT2B pathogenic variant has been identified in an affected family member, prenatal testing for an at-risk pregnancy and preimplantation genetic diagnosis are possible.

PMID: 29697234

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