Micro syndrome in Muslim Pakistan children

doi:10.1016/S0161-6420(00)00540-6

Ophthalmology

Volume 108, Issue 3, March 2001, Pages 491-497

Presented as a poster at the American Academy of Ophthalmology annual meeting, Orlando, Florida, October 1999.

https://doi.org/10.1016/S0161-6420(00)00540-6 Get rights and content

Abstract

Objective

To date, Micro syndrome has been reported in only three children from one family. We describe an additional 14 children from 11 families.

Design

Retrospective case series.

Participants

Fourteen children from 11 families attending one of five British hospitals.

Main outcome measures

The following features were documented: pre- and postoperative eye findings, electrophysiologic analysis, systemic abnormalities, development, neuroimaging, genealogy, geographic origin of family.

Results

We expand and modify the description of ocular and electrophysiologic findings in Micro syndrome. The eye findings of microphakia, microphthalmos, characteristic lens opacity, and atonic pupils were the presenting feature in all infants and were the most reliable diagnostic signs in the immediate postnatal period. Cortical visual impairment, microcephaly, and developmental delay were not always detectable initially; they developed in all children by 6 months of age. Microgenitalia were a useful diagnostic clue in affected males only. Therefore, eye features were more consistently useful in determining diagnosis than dysmorphology or brain imaging. The families of all the children originate from the Muslim population of Northern Pakistan. Inheritance is likely to be autosomal recessive.

Conclusions

Micro syndrome usually presents to the ophthalmologist, who may be able to make the diagnosis on the basis of characteristic eye findings combined with ethnic origin. Initially, the nature and severity of nonophthalmic features are not apparent. Early diagnosis of the underlying condition is important to guide management of the cataracts, glaucoma, and developmental delay. It is helpful for the family and medical staff to be aware of the low level of vision that develops despite optimal ophthalmic intervention. Genetic counseling extending into the wider family is particularly important in view of the high rate of consanguinity.

Section snippets

Patients and methods

Ten infants (patients 1–5 and 10–14, Table 1, Table 2) were referred from eye departments in Birmingham, West Yorkshire, and Bristol between 1996 and 1998 following failure to detect a red reflex in the first few days of life by pediatric colleagues. Subsequent examination of relatives identified a further four children aged between 6 and 16 years in whom the diagnosis had not yet been recognized.

We outline two representative case histories.

Eye findings

The findings presented are the only abnormalities that were always noted by the pediatrician at postnatal examination and were the most likely manifestation of the syndrome to be recognized (Fig 1). We identified several consistent ophthalmic findings that are present in all 14 children, the combination of which is possibly pathognomonic of Micro syndrome: microphthalmos, microphakia, cataract, atonic pupils, mild optic atrophy, and severe cortical vision impairment. The right eye of one child

Discussion

In 1993, Warburg et al3 reported two siblings and a cousin from an inbred Pakistan family who had microcephaly, microcornea, congenital cataracts, optic nerve atrophy, retinal dystrophy, and small pupils bound by posterior synechiae. All the patients were severely mentally handicapped. Other features included hypertrichosis, a beaked nose with a prominent nasal root, and prominent ears. All three patients had absence of the corpus callosum, and one patient was reported to have lissencephaly

References (6)

J.S. Rahi et al.
National cross sectional study of detection of congenital and infantile cataract in the United Kingdomrole of childhood screening and surveillance. The British Congenital Cataract Interest Group
BMJ
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J.B. Bateman
Cataracts
M. Warburg et al.
Autosomal recessive microcephaly, microcornea, congenital cataract, mental retardation, optic atrophy, and hypogenitalism. Micro syndrome
Am J Dis Child
(1993)

There are more references available in the full text version of this article.

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Congenital/childhood cataract is an important cause of lifelong visual impairment. It occasionally arises from trauma, maternal infection, and intrauterine exposure to drugs or radiation. Most cases however have a strong genetic basis and over 100 genes have been associated with cataract formation. A key initial aim of clinicians managing children with cataracts is to determine the precise underlying cause of lens opacification (including distinguishing non-syndromic from syndromic forms). Genomic analysis such as gene panel testing can be particularly helpful, especially in children with bilateral cataracts. In this group of patients, genetic testing can streamline care pathways, inform genetic counselling and facilitate early and more precise interventions. Cataracts caused by genetic abnormalities can be broken down into three main categories:
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  Non-syndromic (isolated) congenital cataract: lens opacities without other ophthalmic or syndromic features.
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  Cataract with other ophthalmic abnormalities: lens opacities combined with other eye phenotypes such as anterior segment dysgenesis, microphthalmia, ectopia lentis or aniridia. Mutations in several genes including some key transcription factors (e.g. FOXE3, PITX3, MAF, PAX6) are detected in a subset of these cases. Persistent fetal vasculature, an important cause of unilateral cataract, can be included in this category although it is only very rarely found to be associated with Mendelian mutations.
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  Cataract associated with multisystemic disorders: lens opacities combined with various metabolic and syndromic disorders; these can be inherited as X-linked (e.g. oculo facio cardio dental syndrome), autosomal recessive (e.g. Warburg Micro syndrome) or autosomal dominant (e.g. Stickler syndrome) traits.
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Loss-of-function mutations in TBC1d20 cause cataracts and male infertility in blind sterile mice and Warburg micro syndrome in humans
2013, American Journal of Human Genetics
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Functional studies have established that WARBM and MS represent a phenotypic spectrum where the clinical outcome is related to the severity of the mutational effects on protein function. Thus, mutations that result in residual protein function cause MS whereas loss-of-function mutations cause WARBM.2–7,9–16 Currently mutations in RAB3GAP1, RAB3GAP2, and RAB18 account for about 50%5 of WARBM cases, suggesting that mutations in additional genes also cause WARBM.
blind sterile (bs) is a spontaneous autosomal-recessive mouse mutation discovered more than 30 years ago. Phenotypically, bs mice exhibit nuclear cataracts and male infertility; genetic analyses assigned the bs locus to mouse chromosome 2. In this study, we first positionally cloned the bs locus and identified a putative causative mutation in the Tbc1d20 gene. Functional analysis established the mouse TBC1D20 protein as a GTPase-activating protein (GAP) for RAB1 and RAB2, and bs as a TBC1D20 loss-of-function mutation. Evaluation of bs mouse embryonic fibroblasts (mEFs) identified enlarged Golgi morphology and aberrant lipid droplet (LD) formation. Based on the function of TBC1D20 as a RABGAP and the bs cataract and testicular phenotypes, we hypothesized that mutations in TBC1D20 may contribute to Warburg micro syndrome (WARBM); WARBM constitutes a spectrum of disorders characterized by eye, brain, and endocrine abnormalities caused by mutations in RAB3GAP1, RAB3GAP2, and RAB18. Sequence analysis of a cohort of 77 families affected by WARBM identified five distinct TBC1D20 loss-of-function mutations, thereby establishing these mutations as causative of WARBM. Evaluation of human fibroblasts deficient in TBC1D20 function identified aberrant LDs similar to those identified in the bs mEFs. Additionally, our results show that human fibroblasts deficient in RAB18 and RAB3GAP1 function also exhibit aberrant LD formation. These findings collectively indicate that a defect in LD formation/metabolism may be a common cellular abnormality associated with WARBM, although it remains unclear whether abnormalities in LD metabolism are contributing to WARBM disease pathology.
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¹: The authors have no proprietary interests in relation to this article and its content.

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Micro syndrome in Muslim Pakistan children1

Abstract

Objective

Design

Participants

Main outcome measures

Results

Conclusions

Section snippets

Patients and methods

Eye findings

Discussion

National cross sectional study of detection of congenital and infantile cataract in the United Kingdomrole of childhood screening and surveillance. The British Congenital Cataract Interest Group

BMJ

Cataracts

Autosomal recessive microcephaly, microcornea, congenital cataract, mental retardation, optic atrophy, and hypogenitalism. Micro syndrome

Am J Dis Child

Micro syndrome in Muslim Pakistan children¹