TUBB4A -Related Leukodystrophy

Norah Nahhas, Alex Conant, Eline Hamilton, Julian Curiel, Cas Simons, Marjo van der Knaap, Adeline Vanderver

Research output: Book/ReportBookAcademic

Abstract

CLINICAL CHARACTERISTICS TUBB4A -related leukodystrophy comprises a phenotypic spectrum in which the MRI findings range from hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) at the severe end to isolated hypomyelination at the mild end. Progressive neurologic findings reflect involvement of the pyramidal tracts (spasticity, brisk deep tendon reflexes, and Babinski sign), extrapyramidal system (rigidity, dystonia, choreoathetosis, oculogyric crisis, and perioral dyskinesia), cerebellum (ataxia, intention tremor, dysmetria), and bulbar function (dysarthria, dysphonia, and swallowing). Cognition is variably affected, usually less severely than motor function. Typically, those with H-ABC present in early childhood (ages one to three years) and those with isolated hypomyelination in later childhood or adulthood. The rate of progression varies with disease severity. DIAGNOSIS/TESTING The diagnosis is established in a proband with characteristic clinical and MRI findings and a heterozygousTUBB4Apathogenic variant identified by molecular genetic testing. MANAGEMENT Treatment of manifestations: Functionally disabling spasticity requires medical management and physical therapy; dystonia requires medical management and – when refractory to medical management – possibly surgical intervention. Swallowing dysfunction may require use of a gastrostomy tube for feeding. Seizures, constipation, and gastroesophageal reflux disease are treated in the routine manner.Prevention of secondary complications:Calcium and vitamin D supplementation as required to prevent osteoporosis; attention to skin care and frequent repositioning to help prevent pressure sores in individuals with decreased mobility; annual flu vaccination; use of routine fall prevention strategies, adaptive equipment (e.g., wheelchairs and walkers), and physical therapy to help prevent secondary injury.Surveillance:Routine evaluations of (1) swallowing and feeding to reduce the risk of aspiration; (2) nutrition to prevent malnutrition; (3) orthopedic and joint integrity to detect joint dislocation and scoliosis. At least yearly: (1) medical evaluations to assess weight and medications; (2) evaluations by specialists in occupational therapy, physical therapy, speech therapy, rehabilitation medicine. Annual neurologic assessment to detect emerging complications. GENETIC COUNSELING TUBB4A -related leukodystrophy is inherited in an autosomal dominant manner. Most affected individuals have the disorder as the result of ade novopathogenic variant. The risk to sibs of a proband with clinically unaffected parents is low but greater than that of the general population because of the possibility of germline mosaicism or somatic and germline mosaicism in a parent. Individuals withTUBB4A-related leukodystrophy are not known to reproduce.
Original languageEnglish
PublisherUniversity of Washington, Seattle
Publication statusPublished - 2016

Cite this

Nahhas, N., Conant, A., Hamilton, E., Curiel, J., Simons, C., van der Knaap, M., & Vanderver, A. (2016). TUBB4A -Related Leukodystrophy. University of Washington, Seattle.
Nahhas, Norah ; Conant, Alex ; Hamilton, Eline ; Curiel, Julian ; Simons, Cas ; van der Knaap, Marjo ; Vanderver, Adeline. / TUBB4A -Related Leukodystrophy. University of Washington, Seattle, 2016.
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title = "TUBB4A -Related Leukodystrophy",
abstract = "CLINICAL CHARACTERISTICS TUBB4A -related leukodystrophy comprises a phenotypic spectrum in which the MRI findings range from hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) at the severe end to isolated hypomyelination at the mild end. Progressive neurologic findings reflect involvement of the pyramidal tracts (spasticity, brisk deep tendon reflexes, and Babinski sign), extrapyramidal system (rigidity, dystonia, choreoathetosis, oculogyric crisis, and perioral dyskinesia), cerebellum (ataxia, intention tremor, dysmetria), and bulbar function (dysarthria, dysphonia, and swallowing). Cognition is variably affected, usually less severely than motor function. Typically, those with H-ABC present in early childhood (ages one to three years) and those with isolated hypomyelination in later childhood or adulthood. The rate of progression varies with disease severity. DIAGNOSIS/TESTING The diagnosis is established in a proband with characteristic clinical and MRI findings and a heterozygousTUBB4Apathogenic variant identified by molecular genetic testing. MANAGEMENT Treatment of manifestations: Functionally disabling spasticity requires medical management and physical therapy; dystonia requires medical management and – when refractory to medical management – possibly surgical intervention. Swallowing dysfunction may require use of a gastrostomy tube for feeding. Seizures, constipation, and gastroesophageal reflux disease are treated in the routine manner.Prevention of secondary complications:Calcium and vitamin D supplementation as required to prevent osteoporosis; attention to skin care and frequent repositioning to help prevent pressure sores in individuals with decreased mobility; annual flu vaccination; use of routine fall prevention strategies, adaptive equipment (e.g., wheelchairs and walkers), and physical therapy to help prevent secondary injury.Surveillance:Routine evaluations of (1) swallowing and feeding to reduce the risk of aspiration; (2) nutrition to prevent malnutrition; (3) orthopedic and joint integrity to detect joint dislocation and scoliosis. At least yearly: (1) medical evaluations to assess weight and medications; (2) evaluations by specialists in occupational therapy, physical therapy, speech therapy, rehabilitation medicine. Annual neurologic assessment to detect emerging complications. GENETIC COUNSELING TUBB4A -related leukodystrophy is inherited in an autosomal dominant manner. Most affected individuals have the disorder as the result of ade novopathogenic variant. The risk to sibs of a proband with clinically unaffected parents is low but greater than that of the general population because of the possibility of germline mosaicism or somatic and germline mosaicism in a parent. Individuals withTUBB4A-related leukodystrophy are not known to reproduce.",
keywords = "4A chain, ABC), Hypomyelination with Atrophy of Basal Ganglia and, Related Hypomyelinating Leukodystrophy, Related Isolated Hypomyelination, Related Leukodystrophy, TUBB4A, Tubulin beta",
author = "Norah Nahhas and Alex Conant and Eline Hamilton and Julian Curiel and Cas Simons and {van der Knaap}, Marjo and Adeline Vanderver",
year = "2016",
language = "English",
publisher = "University of Washington, Seattle",

}

Nahhas, N, Conant, A, Hamilton, E, Curiel, J, Simons, C, van der Knaap, M & Vanderver, A 2016, TUBB4A -Related Leukodystrophy. University of Washington, Seattle.

TUBB4A -Related Leukodystrophy. / Nahhas, Norah; Conant, Alex; Hamilton, Eline; Curiel, Julian; Simons, Cas; van der Knaap, Marjo; Vanderver, Adeline.

University of Washington, Seattle, 2016.

Research output: Book/ReportBookAcademic

TY - BOOK

T1 - TUBB4A -Related Leukodystrophy

AU - Nahhas, Norah

AU - Conant, Alex

AU - Hamilton, Eline

AU - Curiel, Julian

AU - Simons, Cas

AU - van der Knaap, Marjo

AU - Vanderver, Adeline

PY - 2016

Y1 - 2016

N2 - CLINICAL CHARACTERISTICS TUBB4A -related leukodystrophy comprises a phenotypic spectrum in which the MRI findings range from hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) at the severe end to isolated hypomyelination at the mild end. Progressive neurologic findings reflect involvement of the pyramidal tracts (spasticity, brisk deep tendon reflexes, and Babinski sign), extrapyramidal system (rigidity, dystonia, choreoathetosis, oculogyric crisis, and perioral dyskinesia), cerebellum (ataxia, intention tremor, dysmetria), and bulbar function (dysarthria, dysphonia, and swallowing). Cognition is variably affected, usually less severely than motor function. Typically, those with H-ABC present in early childhood (ages one to three years) and those with isolated hypomyelination in later childhood or adulthood. The rate of progression varies with disease severity. DIAGNOSIS/TESTING The diagnosis is established in a proband with characteristic clinical and MRI findings and a heterozygousTUBB4Apathogenic variant identified by molecular genetic testing. MANAGEMENT Treatment of manifestations: Functionally disabling spasticity requires medical management and physical therapy; dystonia requires medical management and – when refractory to medical management – possibly surgical intervention. Swallowing dysfunction may require use of a gastrostomy tube for feeding. Seizures, constipation, and gastroesophageal reflux disease are treated in the routine manner.Prevention of secondary complications:Calcium and vitamin D supplementation as required to prevent osteoporosis; attention to skin care and frequent repositioning to help prevent pressure sores in individuals with decreased mobility; annual flu vaccination; use of routine fall prevention strategies, adaptive equipment (e.g., wheelchairs and walkers), and physical therapy to help prevent secondary injury.Surveillance:Routine evaluations of (1) swallowing and feeding to reduce the risk of aspiration; (2) nutrition to prevent malnutrition; (3) orthopedic and joint integrity to detect joint dislocation and scoliosis. At least yearly: (1) medical evaluations to assess weight and medications; (2) evaluations by specialists in occupational therapy, physical therapy, speech therapy, rehabilitation medicine. Annual neurologic assessment to detect emerging complications. GENETIC COUNSELING TUBB4A -related leukodystrophy is inherited in an autosomal dominant manner. Most affected individuals have the disorder as the result of ade novopathogenic variant. The risk to sibs of a proband with clinically unaffected parents is low but greater than that of the general population because of the possibility of germline mosaicism or somatic and germline mosaicism in a parent. Individuals withTUBB4A-related leukodystrophy are not known to reproduce.

AB - CLINICAL CHARACTERISTICS TUBB4A -related leukodystrophy comprises a phenotypic spectrum in which the MRI findings range from hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) at the severe end to isolated hypomyelination at the mild end. Progressive neurologic findings reflect involvement of the pyramidal tracts (spasticity, brisk deep tendon reflexes, and Babinski sign), extrapyramidal system (rigidity, dystonia, choreoathetosis, oculogyric crisis, and perioral dyskinesia), cerebellum (ataxia, intention tremor, dysmetria), and bulbar function (dysarthria, dysphonia, and swallowing). Cognition is variably affected, usually less severely than motor function. Typically, those with H-ABC present in early childhood (ages one to three years) and those with isolated hypomyelination in later childhood or adulthood. The rate of progression varies with disease severity. DIAGNOSIS/TESTING The diagnosis is established in a proband with characteristic clinical and MRI findings and a heterozygousTUBB4Apathogenic variant identified by molecular genetic testing. MANAGEMENT Treatment of manifestations: Functionally disabling spasticity requires medical management and physical therapy; dystonia requires medical management and – when refractory to medical management – possibly surgical intervention. Swallowing dysfunction may require use of a gastrostomy tube for feeding. Seizures, constipation, and gastroesophageal reflux disease are treated in the routine manner.Prevention of secondary complications:Calcium and vitamin D supplementation as required to prevent osteoporosis; attention to skin care and frequent repositioning to help prevent pressure sores in individuals with decreased mobility; annual flu vaccination; use of routine fall prevention strategies, adaptive equipment (e.g., wheelchairs and walkers), and physical therapy to help prevent secondary injury.Surveillance:Routine evaluations of (1) swallowing and feeding to reduce the risk of aspiration; (2) nutrition to prevent malnutrition; (3) orthopedic and joint integrity to detect joint dislocation and scoliosis. At least yearly: (1) medical evaluations to assess weight and medications; (2) evaluations by specialists in occupational therapy, physical therapy, speech therapy, rehabilitation medicine. Annual neurologic assessment to detect emerging complications. GENETIC COUNSELING TUBB4A -related leukodystrophy is inherited in an autosomal dominant manner. Most affected individuals have the disorder as the result of ade novopathogenic variant. The risk to sibs of a proband with clinically unaffected parents is low but greater than that of the general population because of the possibility of germline mosaicism or somatic and germline mosaicism in a parent. Individuals withTUBB4A-related leukodystrophy are not known to reproduce.

KW - 4A chain

KW - ABC)

KW - Hypomyelination with Atrophy of Basal Ganglia and

KW - Related Hypomyelinating Leukodystrophy

KW - Related Isolated Hypomyelination

KW - Related Leukodystrophy

KW - TUBB4A

KW - Tubulin beta

M3 - Book

BT - TUBB4A -Related Leukodystrophy

PB - University of Washington, Seattle

ER -

Nahhas N, Conant A, Hamilton E, Curiel J, Simons C, van der Knaap M et al. TUBB4A -Related Leukodystrophy. University of Washington, Seattle, 2016.