Menkes syndrome E83.0

Author: Prof. Dr. med. Peter Altmeyer

Last updated on: 29.10.2020

Synonym(s)

Curly hair syndrome; Kinky hair disease; Kinky-hair-disease; menkes disease; Menke`s kinky hair syndrome; Menkes steel hair disease; Menkes Syndrome; OMIM 30001; OMIN 309400; Pili torti with copper deficiency; Steel Hair Syndrome; Steely-hair-syndrome; Trichopoliodystrophy

History
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Menkes, 1962

Definition
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X-linked recessive, progressive, neurodegenerative disease due to copper absorption disorders in the intestine and impaired copper transport in tissue. Among other things, this leads to disorders of copper-dependent tyrosinase (depigmentation of hair), increase in free sulfhydryl groups in keratin with consecutive impairment of the disulfide bridges of the keratin molecules (brittleness of hair).

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Occurrence/Epidemiology
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Incidence: 1:298,000 live births.

Etiopathogenesis
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X-linked recessive mutations of the ATP7a gene (Cu-transporting ATPase, alpha polypeptide gene; gene locus Xq12-Xq13.3). The defective ATP7a gene codes for a copper-transporting ATPase, which is responsible for the intracellular transport of this trace element (Fujisawa C et al. 2019). Many symptoms of kinky hair disease can be attributed to the reduced activity of 5 copper-dependent enzymes, including lysyl oxidase and tyrosinase.

Manifestation
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Mostly 5th week of life to 5th month of life. Boys are preferentially infested.

Localization
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Head hair, eyebrows.

Clinical features
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Pale skin with pronounced cutis laxa.

Pili torti, sparse, low-pigment, bristly, lackluster, kinked hair.

Physical and psychomotor retardation, cramps, often hypothermia episodes. Growth disorders with scurvy bone changes. Progressive signs of decerebration. Mask-like face with roundish, drooping cheeks, often a rigid gaze.

Brain: Dilatation of the lateral ventricles, hypoplasia or atrophy of cerebrum and cerebellum, demyelination, leukomalacia, subdural hematomas.

Skeleton: metaphyseal gouging and spur formation, diaphyseal periosteal deposits, switch bones on the skull, osteoporosis, rarely platyspondylia.

Vessels: Tortuosity, dilatation (jump in calibre) and/or proliferation as well as corkscrew-like torsion of the intracranial and visceral arteries; bladder diverticula, vesicoureteral reflux.

Laboratory
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Pathologically deep serum copper and coeruloplasmin, abnormally increased copper uptake by cultured fibroblasts

Diagnosis
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Prenatal diagnosis from chorionic villi is more reliable than from amniotic fluid cells.

Chorionic villi: copper content increased (several times the norm), copper bound to trophoblast cell membrane is detectable by electron microscopy.

Amniotic fluid cells: increased copper absorption.

Therapy
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Under copper substitution (copper histidinate) improvement of hair structure and pigmentation are described. This cannot improve the prognosis.

Progression/forecast
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The course is determined by cramping and airway infections (immobilization, aspiration). Death in infancy or toddlers, mostly in the 4th to 5th year of life. Very rarely survival into adulthood is described.

Note(s)
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The Ocipital horn syndrome has been known in the past as"cutis-laxa". However, it has the same genetic defect as the Menkes syndrome (Kinky hair disease), so that it can be classified as a negative variant of this syndrome.

Literature
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Banci L et al (2004) Solution structure and backbone dynamics of the Cu(I) and apo forms of the second metal-binding domain of the Menkes protein ATP7A. Biochemistry 43: 3396-3403
Fujisawa C et al(2019) ATP7A mutations in 66 Japanese patients with Menkes disease and carrierdetection
: A gene analysis. Pediatr Int 61:345-350.
Garnica A et al (1994) Copper-Histidine treatment of menkes disease. J Pediatr 125: 336-337
Kodama H et al (2003) Biochemical indicator for evaluation of connective tissue abnormalities in Menkes' disease. J Pediatr 142: 726-728
Menkes JH, Alter M, Steigleder GK et al (1962) A sex-linked recessive disorder with retardation of growth, peculiar hair, and focal cerebral and cerebellar degeneration. Pediatrics 29: 764-779
Tonnesen T, Kleijer WJ, Horn N (1991) Incidence of Menkes disease. Hum Genet 86: 408-410
Tonnesen T, Petterson A, Kruse TA et al (1992) Multipoint linkage analysis in Menkes disease. At J Hum Genet 50: 1012-1017
Vulpe C, Levinson B, Whitney S et al (1993) Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase. Nat Genet 3: 7-13
Zaffanello M et al (2003) Rare urological abnormalities in 2 cases of Menkes' syndrome. J Urol 170: 1335