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Congenital cerebral hypomyelination; network for Pelizaeus-Merzbacher disease and related disorders

  • Inherited white matter disorders
  • Congenital cerebral hypomyelination

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Guidelines on Hereditary Leukodystrophies

Hypomyelination and congenital cataract (HCC; HLD5, OMIM #610532)

Disease description: Hypomyelination and congenital cataract is an autosomal recessive inherited disease. Its clinical presentation comprises bilateral congenital cataracts along with gradually progressing ataxia, spasticity, and moderate to severe intellectual disability from 1 year of age. Magnetic resonance imaging shows signs of hypomyelination. The causative gene is FAM126A.

1. Concept

Definition

Hypomyelination and congenital cataract (HCC) was first reported in 2006, when a single case of cerebral leukodystrophy and cataract was described as a new autosomal recessive inherited form of cerebral leukodystrophy. It is very rare, with only around 20 reported cases to date, and no case has been reported in Japan. It presents as congenital cerebral leukodystrophy with bilateral congenital cataracts together with peripheral neuropathy.

Epidemiology

There has been no epidemiological study of the incidence of this disease. An extremely rare condition, only around 20 cases have been reported worldwide, and there have been no reports of a confirmed genetic diagnosis in Japan.

Etiology and pathophysiology

The mutation is identified by DNA sequencing of the causative gene FAM126A (7p15.3), which has been implicated in the synthesis of phosphatidylinositol 4-phosphate, a cell membrane constituent (Baskin JM). FAM126A, a component of the phosphatidylinositol 4-phosphate kinase complex, is an isoform of FAM126, which is abundant in oligodendrocytes. FAM126A deficiency prevents the synthesis of phosphatidylinositol 4-phosphate and the phosphoinositides of which it is a precursor, and this is believed to prevent the production of the broad membranes essential for myelination.

Clinical symptoms

Cataracts are noticed within 1 month after birth, and although affected infants become able to support their head and sit up as normal, developmental delay becomes apparent after age 1 year when they do not learn to walk. They become able to walk with assistance by around age 2 but never become capable of walking independently. Their condition gradually regresses, with almost all patients losing the ability to walk by adulthood. Pyramidal signs appear in all cases, and the presence of pathological reflexes with reduced normal reflexes is characteristic. Cerebellar symptoms appear in 90% of patients, and neurological symptoms are present in the form of hypotonia and atrophy of the distal leg muscles. Case reports do not mention any corticobasal symptoms (such as dystonia or athetosis). Intellectual developmental delay is mild to moderate, and seizures other than febrile convulsions have been reported in 2 patients.

Imaging and other investigations

Peripheral nerve conduction velocity is reduced in 90% of patients, and peripheral nerve biopsy shows a decrease in myelinated fibers together with signs of dysmyelination on electron microscopy. On magnetic resonance imaging, diffuse hyperintensity is evident on T2-weighted imaging as well as isointensity or slight hyperintensity on T1-weighted imaging, but some periventricular regions are strongly hyperintense on T2-weighted imaging and hypointense on T1-weighted imaging, suggesting that the white matter in these areas may have a high water content.

Genetic diagnosis

Mutations in both alleles are identified by DNA sequencing of the causative gene FAM126A (7p15.3). Only 12 mutations have been reported to date, comprising 3 point mutations (2 amino acid substitutions and 1 nonsense mutation), 4 splicing defects, 4 small deletions or insertions, and 1 exon deletion.

2. Treatment and care

As there is currently no curative treatment for congenital cerebral leukodystrophy, symptomatic care is provided.

3. Diet and nutrition

Treatment is provided according to the symptoms that present.

4. Prognosis

There has been no survey of the natural history of this condition, so its details are unknown. Almost all affected patients require a wheelchair as they are or become unable to walk.

5. Differential diagnosis

HCC must be differentiated from other congenital cerebral leukodystrophies. Pelizaeus-Merzbacher disease, which is caused by a PLP1 mutation, is an X-linked condition; in most cases, neurological symptoms including impaired motor development, intellectual disability, and nystagmus appear before age 1. Most patients exhibit gradual development.

6. Recent topics

Work is underway to identify the functions of the causative gene FAM126A to clarify the formerly unknown pathophysiology of HCC (Baskin JM). FAM126A has been implicated in the synthesis of phosphatidylinositol 4-phosphate, a cell membrane constituent. FAM126A, a component of the phosphatidylinositol 4-phosphate kinase complex, is an isoform of FAM126, which is abundant in oligodendrocytes. FAM126A deficiency prevents the synthesis of phosphatidylinositol 4-phosphate and the phosphoinositides of which it is a precursor. Its absence is believed to prevent the production of the broad membranes that are essential for myelination.

References (Unless otherwise noted at the end, all are evidence level 6.)
  1. Baskin JM, Wu X, Christiano R, Oh MS, Schauder CM, Gazzerro E, Messa M, Baldassari S, Assereto S, Biancheri R, Zara F, Minetti C, Raimondi A, Simons M, Walther TC, Reinisch KM, De Camilli P. The leukodystrophy protein FAM126A (hyccin) regulates PtdIns(4)P synthesis at the plasma membrane. Nat Cell Biol. 2016; 18(1): 132-138. doi: 10.1038/ncb3271.
  2. Biancheri R, Zara F, Bruno C, Gazzerro E, Rossi A, van der Knaap MS, Minetti C. Hypomyelination and Congenital Cataract. 2008 Oct 14 [updated 2015 Jun 4]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mefford HC, Stephens K, Amemiya A, Ledbetter N, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available at: http://www.ncbi.nlm.nih.gov/books/NBK2587/ PubMed PMID: 20301737.
  3. Traverso M, Assereto S, Gazzerro E, Savasta S, Abdalla EM, Rossi A, Baldassari S, Fruscione F, Ruffinazzi G, Fassad MR, El Beheiry A, Minetti C, Zara F, Biancheri R. Novel FAM126A mutations in hypomyelination and congenital cataract disease. Biochem Biophys Res Commun 2013; 439(3): 369-372. doi: 10.1016/j.bbrc.2013.08.077.(5)
  4. Traverso M, Yuregir OO, Mimouni-Bloch A, Rossi A, Aslan H, Gazzerro E, Baldassari S, Fruscione F, Minetti C, Zara F, Biancheri R. Hypomyelination and congenital cataract: identification of novel mutations in two unrelated families. Eur J Paediatr Neurol 2013; 17(1): 108-111. doi: 10.1016/j.ejpn.2012.06.004.(5)
  5. Biancheri R, Zara F, Rossi A, Mathot M, Nassogne MC, Yalcinkaya C, Erturk O, Tuysuz B, Di Rocco M, Gazzerro E, Bugiani M, van Spaendonk R, Sistermans EA, Minetti C, van der Knaap MS, Wolf NI. Hypomyelination and congenital cataract: broadening the clinical phenotype. Arch Neurol 2011; 68(9): 1191-1194. doi: 10.1001/archneurol.2011.201.(4b)
  6. Rossi A, Biancheri R, Zara F, Bruno C, Uziel G, van der Knaap MS, Minetti C, Tortori-Donati P. Hypomyelination and congenital cataract: neuroimaging features of a novel inherited white matter disorder. AJNR Am J Neuroradiol 2008; 29(2): 301-305.(4b)
  7. Ugur SA, Tolun A. A deletion in DRCTNNB1A associated with hypomyelination and juvenile onset cataract. Eur J Hum Genet 2008; 16(2): 261-264.(5)
  8. Biancheri R, Zara F, Bruno C, Rossi A, Bordo L, Gazzerro E, Sotgia F, Pedemonte M, Scapolan S, Bado M, Uziel G, Bugiani M, Lamba LD, Costa V, Schenone A, Rozemuller AJ, Tortori-Donati P, Lisanti MP, van der Knaap MS, Minetti C. Phenotypic characterization of hypomyelination and congenital cataract. Ann Neurol 2007; 62(2): 121-127.(4b)
  9. Zara F, Biancheri R, Bruno C, Bordo L, Assereto S, Gazzerro E, Sotgia F, Wang XB, Gianotti S, Stringara S, Pedemonte M, Uziel G, Rossi A, Schenone A, Tortori-Donati P, van der Knaap MS, Lisanti MP, Minetti C. Deficiency of hyccin, a newly identified membrane protein, causes hypomyelination and congenital cataract. Nat Genet 2006; 38(10): 1111-1113.(5)
Literature search

PubMed

  • Hypomyelination[All Fields] AND ("congenital"[Subheading] OR "congenital"[All Fields]) AND ("cataract"[MeSH Terms] OR "cataract"[All Fields])
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Igaku Chūō Zasshi

  • (白内障-先天性/TH or 先天性白内障/AL) and (髄鞘/TH or 髄鞘/AL)　2 results