hypotonia

Retinitis Pigmentosa and Mental Retardation

Clinical Characteristics
Ocular Features: 

The lenses may have pleomorphic white axial opacities but in other patients can be totally opacified.  Optic atrophy is present and vision may be reduced to light perception but nystagmus is absent.  Evidence suggests that vision loss is progressive.  Some patients have extensive posterior synechiae while others have been noted to have sluggish pupils.  High myopia is a feature. The retinal pigmentation has a typical retinitis pigmentosa picture with attenuated retinal vessels and equatorial bone spicule pigmentation located in the midperiphery while the macula can have a bull’s eye appearance.   

Systemic Features: 

Early development may seem normal but developmental milestones are usually delayed.  Postnatal microcephaly and growth deficiency with mental retardation and early hypotonia are typical features.  The mental retardation may be severe.  Scoliosis and arachnodactyly have been noted and hypogonadism has been reported.  Speech may not develop and mobility is sometimes limited.

Genetics

The family pattern suggests autosomal recessive inheritance.  Homozygosity mapping has identified in a region of chromosome 8 (8q21.2-22.1) that overlaps the region for Cohen syndrome () but no specific mutated gene has been identified.      

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

None.

References
Article Title: 

Chorioretinal dysplasia, lymphedema, and microcephaly

Clinical Characteristics
Ocular Features: 

The congenital lymphedema results in thickened and ptotic eyelids with prominent epicanthal folds.  Congenital ptosis is not uncommon in the general population in the absence of lymphedema so that this feature by itself is insufficient to diagnose this syndrome.  Retinal folds with variable degrees of pigmentary changes are often present.  Narrowed retinal vessels, atrophic nerve heads and progressive chorioretinopathy have been reported.  Visual acuity is often reduced, sometimes severely, and nystagmus may be present.

Systemic Features: 

Coarse hair follicles over the dorsum of the hands and feet and white nails when combined with the thickened, ptotic eyelids suggest the presence of lymphedema.  The hair pattern is often altered on the arms, nape of the neck, and the back.  White lines in the palms are also suggestive.  The 'facial phenotype' includes full cheeks, flat nasal bridge and underdeveloped supraorbital ridges, up slanting palpebral fissures, broad nose with rounded tip, anteverted nares, and a long philtrum, thin upper lip, and sometimes micrognathia. The ears may appear large.  Children with this syndrome are often hypotonic during the newborn period but this feature is less evident later in childhood and improves more rapidly than the resolution of the lymphedema. The lymphedema usually improves during early childhood and is often confined to the dorsum of the hands and feet at that time.  Psychomotor development is variably delayed and some but not all patients are mentally retarded. Microcephaly is a consistent feature.

Not all features are present in all patients and, specifically, there are often microcephalic relatives who lack other signs.

Genetics

This is an autosomal dominant disorder which may consist of more than one entity but at least some cases result from heterozygous mutations in KIF11 (10q23.33).  The gene encodes a member of the kinesin family of proteins responsible for cytoplasmic mechanisms that are essential for spindle assembly and function as well in transportation of other intracellular organelles.  Mutations in this gene have also been implicated in familial exudative vitreoretinopathy (FEVR) and there is phenotypic overlap with the condition described here.

It is not unusual for microcephalic individuals to also have chorioretinal dysplasia and/or pigmentary retinopathy.  See microcephaly, chorioretinal dysplasia, mental retardation (156590), for a somewhat similar autosomal dominant condition, as well as microcephaly with chorioretinopathy, AR (251270) for an autosomal recessive condition with this combination.  Neither of these conditions is associated with congenital lymphedema, however.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Phenotypic Overlap Between Familial Exudative Vitreoretinopathy and Microcephaly, Lymphedema, and Chorioretinal Dysplasia Caused by KIF11 Mutations

Robitaille JM, Gillett RM, LeBlanc MA, Gaston D, Nightingale M, Mackley MP, Parkash S, Hathaway J, Thomas A, Ells A, Traboulsi EI, Heon E, Roy M, Shalev S, Fernandez CV, MacGillivray C, Wallace K, Fahiminiya S, Majewski J, McMaster CR, Bedard K. Phenotypic Overlap Between Familial Exudative Vitreoretinopathy and Microcephaly, Lymphedema, and Chorioretinal Dysplasia Caused by KIF11 Mutations. JAMA Ophthalmol. 2014 Aug 14.

PubMed ID: 
25124931

Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR): review of phenotype associated with KIF11 mutations

Jones GE, Ostergaard P, Moore AT, Connell FC, Williams D, Quarrell O, Brady AF, Spier I, Hazan F, Moldovan O, Wieczorek D, Mikat B, Petit F, Coubes C, Saul RA, Brice G, Gordon K, Jeffery S, Mortimer PS, Vasudevan PC, Mansour S. Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR): review of phenotype associated with KIF11 mutations. Eur J Hum Genet. 2013 Nov 27.  [Epub ahead of print).

PubMed ID: 
24281367

Mutations in KIF11 Cause Autosomal-Dominant Microcephaly Variably Associated with Congenital Lymphedema and Chorioretinopathy

Ostergaard P, Simpson MA, Mendola A, Vasudevan P, Connell FC, van Impel A, Moore AT, Loeys BL, Ghalamkarpour A, Onoufriadis A, Martinez-Corral I, Devery S, Leroy JG, van Laer L, Singer A, Bialer MG, McEntagart M, Quarrell O, Brice G, Trembath RC, Schulte-Merker S, Makinen T, Vikkula M, Mortimer PS, Mansour S, Jeffery S. Mutations in KIF11 Cause Autosomal-Dominant Microcephaly Variably Associated with Congenital Lymphedema and Chorioretinopathy. Am J Hum Genet. 2012 Jan 24. [Epub ahead of print].

PubMed ID: 
22284827

Cataracts, Ataxia, Short Stature, and Mental Retardation

Clinical Characteristics
Ocular Features: 

Cataracts are present in both sexes but the opacification is more extensive in males and only partial in females.  The cataracts are congenital in males but apparently develop later in females who complain of blurred vision from early childhood or during teenage years.  The lenses in females have punctate and pulverulent opacities as well as posterior subcapsular sclerosis.  Vision has been estimated as hand motion from early childhood in boys and about 20/40 in females in the first two decades of life.

Systemic Features: 

Males have mild to moderate mental retardation, muscle hypotonia and weakness with postural tremor.  Their standing position is broad-based and they are unable to sit or stand otherwise without some support.  They are usually unable to walk unassisted.  Speech is dysarthric and its development is delayed.  Females are neurologically normal.

Genetics

A locus containing the disease allele at Xpter-q13.1 cosegregates with the cataract phenotype in both sexes.  The gene mutation has not been identified.  This can be called an X-linked recessive disorder with partial expression in heterozygous females.

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

Cataract surgery may be indicated in young females and may be beneficial in infant boys.

References
Article Title: 

RAB18 Deficiency

Clinical Characteristics
Ocular Features: 

Microphthalmia with microcornea, lens opacities, small and unresponsive pupils, and optic atrophy are the outstanding ocular features of this syndrome.  The eyes appear deeply set.  Some but not all have ERG evidence of rod and cone dysfunction.  The VEP is usually abnormal.  Short palpebral fissures have been described. 

Systemic Features: 

Patients with the micro syndrome have many somatic and neurologic abnormalities.  Infants usually have feeding problems that is sometimes accompanied by gastroesophageal reflux.  Some degree of psychomotor retardation and developmental delays is common.  Both spasticity and hypotonia have been described.  Some patients have seizures.  Facial hypertrichosis, anteverted ears, and a broad nasal bridge are often noted.   There may be absence of the corpus callosum while diffuse cortical and subcortical atrophy, microgyria, and pachygyria may be evident on MRI imaging.  Hypogenitalism may be a feature in both sexes.  Males may also have cryptorchidism and a micropenis while females can have hypoplasia of the labia minora and clitoris and a small introitus.  Microcephaly is inconsistently present. 

Genetics

This is a clinically and genetically heterogeneous disorder caused by homozygous mutations in at least 4 genes: RAB3GAP1 (WARBM1), RAB3GAP2 (WARBM2), RAB18 (WARBM3), and TBC1D20 (WARBM4).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available.  Vision remains subnormal even after cataracts are removed.  Nutrition may be improved with placement of a gastrostomy tube.

References
Article Title: 

New RAB3GAP1 mutations in patients with Warburg Micro Syndrome from different ethnic backgrounds and a possible founder effect in the Danish

Morris-Rosendahl DJ, Segel R, Born AP, Conrad C, Loeys B, Brooks SS, M?oller L,Zeschnigk C, Botti C, Rabinowitz R, Uyanik G, Crocq MA, Kraus U, Degen I, Faes F. New RAB3GAP1 mutations in patients with Warburg Micro Syndrome from different ethnic backgrounds and a possible founder effect in the Danish. Eur J Hum Genet. 2010 Oct;18(10):1100-6.

PubMed ID: 
20512159

Pierson Syndrome

Clinical Characteristics
Ocular Features: 

Microcoria is the most consistent ocular feature but is not present in some families.  It is congenital and sometimes seen with iris hypoplasia.  Glaucoma and lens opacities (including posterior lenticonus sometimes) are present in one-fourth of patients.  Corneal size varies with some patients having apparent macrocornea which can lead to the mistaken diagnosis of buphthalmos.  Pigment mottling and clumping is common in the retina and the ERG can show changes characteristic of cone-rod dystrophy.  Retinal thinning is often present as well.  Non-rhegmatogenous retinal detachments occur in 24% of patients and optic atrophy is seen in some individuals.  There is considerable interocular, intrafamilial, and interfamilial variability in these signs. 

Systemic Features: 

The primary and most consistent systemic problem is progressive renal disease. Congenital nephrotic syndrome with proteinuria, hypoalbuminemia and hypertension is characteristic.  Renal failure eventually occurs although the rate of progression varies. Most patients require a renal transplant for end-stage kidney disease in the first decade of life.  Kidney histology shows glomerulosclerosis, peritubular scarring, and diffuse mesangial sclerosis.  Hypotonia and muscle weakness are sometimes present and congenital myasthenia has been reported.  Severe global psychomotor retardation is common and many infants never achieve normal milestones. 

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in the LAMB2 gene located at 3p21.  The normal gene encodes laminin beta-2 that is strongly expressed in intraocular muscles which may explain the hypoplasia of ciliary and pupillary muscles in Pierson syndrome.  Mutations in this gene are often associated with nephronophthisis but ocular abnormalities are not always present. 

Microcoria is also a feature of the autosomal dominant ocular condition known as congenital microcoria (156600).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Kidney replacement can restore renal function.  Glaucoma, cataracts, and retinal detachments require the usual treatment but patient selection is important due to the neurological deficits.  Lifelong monitoring is essential. 

References
Article Title: 

Ocular findings in a case of Pierson syndrome with a novel mutation in laminin ß2 gene

Arima M, Tsukamoto S, Akiyama R, Nishiyama K, Kohno RI, Tachibana T, Hayashida A, Murayama M, Hisatomi T, Nozu K, Iijima K, Ohga S, Sonoda KH. Ocular findings in a case of Pierson syndrome with a novel mutation in laminin ss2 gene. J AAPOS. 2018 Aug 16. pii: S1091-8531(18)30497-X. doi: 10.1016/j.jaapos.2018.03.016. [Epub ahead of print].

PubMed ID: 
30120985

Ophthalmological aspects of Pierson syndrome

Bredrup C, Matejas V, Barrow M, Bl?deghov?deg K, Bockenhauer D, Fowler DJ, Gregson RM, Maruniak-Chudek I, Medeira A, Mendon?ssa EL, Kagan M, Koenig J, Krastel H, Kroes HY, Saggar A, Sawyer T, Schittkowski M, Swietli?Nski J, Thompson D, VanDeVoorde RG, Wittebol-Post D, Woodruff G, Zurowska A, Hennekam RC, Zenker M, Russell-Eggitt I. Ophthalmological aspects of Pierson syndrome. Am J Ophthalmol. 2008 Oct;146(4):602-611.

PubMed ID: 
18672223

GM1 Gangliosidosis

Clinical Characteristics
Ocular Features: 

Based on clinical manifestations, three types have been described: type I or infantile form, type II or late-infantile/juvenile form, and type III or adult/chronic form but all are due to mutations in the same gene.  Only the infantile form has the typical cherry red spot in the macula but is present in only about 50% of infants.  The corneal clouding is due to intracellular accumulations of mucopolysaccharides in corneal epithelium and keratan sulfate in keratocytes.  Retinal ganglion cells also have accumulations of gangliosides.  Decreased acuity, nystagmus, strabismus and retinal hemorrhages have been described. 

Systemic Features: 

Infants with type I disease are usually hypotonic from birth but develop spasticity, psychomotor retardation, and hyperreflexia within 6 months.  Early death from cardiopulmonary disease or infection is common.  Hepatomegaly, coarse facial features, brachydactyly, and cardiomyopathy with valvular dysfunction are common.  Dermal melanocytosis has also been described in infants in a pattern some have called Mongolian spots.  Skeletal dysplasia is a feature and often leads to vertebral deformities and scoliosis.  The ears are often large and low-set, the nasal bridge is depressed, the tongue is enlarged and frontal bossing is often striking.  Hirsutism, coarse skin, short digits, and inguinal hernias are common.

The juvenile form, type II, has a later onset with psychomotor deterioration, seizures and skeletal changes apparent between 7 and 36 months and death in childhood.  Visceral involvement and cherry-red spots are usually not present. 

Type III, or adult form, is manifest later in the first decade or even sometime by the 4th decade.  Symptoms and signs are more localized.  Neurological signs are evident as dystonia or speech and gait difficulties.  Dementia, parkinsonian signs, and extrapyramidal disease are late features.  No hepatosplenomegaly, facial dysmorphism, or cherry red spots are present in most individuals. Lifespan may be normal in this type. 

Genetics

This is an autosomal recessive lysosomal storage disease secondary to a mutations in GLB1 (3p21.33).  It is allelic to Morquio B disease (MPS IVB) (253010).  The mutations in the beta-galactosidase-1 gene result in intracellular accumulation of GM1 ganglioside, keratan sulfate, and oligosaccharides.  The production of the enzyme varies among different mutations likely accounting for the clinical heterogeneity. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment that effectively alters the disease course. 

References
Article Title: 

Lowe Oculocerebrorenal Syndrome

Clinical Characteristics
Ocular Features: 

Lens development is abnormal from the beginning secondary to abnormal migration of lens epithelium which has been described in fetuses by 20-24 weeks of gestation.  This leads to some degree of opacification in 100% of affected males.  The lens opacities may be polar or nuclear in location but complete opacification also occurs.   Leukocoria, miosis, microphthalmos and a shallow anterior chamber has been noted in neonates.  The cataractous lenses may be small and abnormally formed.  Glaucoma is present in more than half of affected males with onset by the age of 6 years and may be difficult to control.  Conjunctival and corneal keloids are found in about one-fourth of patients.

Adult female carriers characteristically have peripheral cortical opacities, appearing in a radial configuration.  These 'snowflake' opacities seldom cause visual symptoms.   It has been proposed that slit lamp examinations for such opacities can accurately determine the carrier status of females.

Systemic Features: 

Mental retardation, hypotonia, short stature, and developmental delays are common.  Seizures and behavior problems are seen in older children.  The renal defect secondary to defective phosphatidylinositol 4, 5-biphosphate 5- phosphatase results in a Fanconi-type aminoaciduria beginning late in the first year of life.  The phosphaturia leads to hypophosphatemia and eventually renal rickets.  Proteinuria, polyuria, as well as bicarbonate, sodium and potassium wasting with tubular acidosis are all part of the urinary profile.  Some patients have dental cysts and/or defective dentin.

Genetics

The mutation causing this X-linked disorder is in the OCRL gene located at Xq26.1.  New mutations have been found among nearly one-third of affected males.  

Another X-linked disorder with similar but less severe kidney disease, Dent disease 2 (300555), has been found to have mutations in the same gene.  However, none of the ocular features are present.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cataracts need to be removed before sensory nystagmus and amblyopia develop.  Fluid and electrolyte balance must be maintained.  Growth hormone can be used in selected patients.  Supportive systemic care is necessary in most cases.  Lifelong kidney and ocular monitoring is recommended.

References
Article Title: 

Smith-Lemli-Opitz Syndrome

Clinical Characteristics
Ocular Features: 

A large number of ocular anomalies have been found in SLO syndrome but the most common is blepharoptosis of some degree.  No consistent pattern of ocular abnormalities has been reported.  Atrophy and hypoplasia of the optic nerve, strabismus, nystagmus, and cataracts may be present.   Abnormally low concentrations of cholesterol and cholesterol precursors have been found in all ocular tissues studied.

Systemic Features: 

This is a syndrome of multiple congenital anomalies.  Among these are dwarfism, micrognathia, hard palate anomalies, hypotonia, anomalies of the external genitalia, polysyndactyly, microcephaly, and mental retardation.  It has been suggested that many individuals have a characteristic behavioral profile consisting of cognitive delays, hyperreactivity, irritability, language deficiency, and autism spectrum behaviors.  Some individuals exhibit aspects of self destructive behavior.  Tissue levels of cholesterol are low.

Genetics

SLO syndrome is an autosomal recessive disorder resulting from mutations in the sterol delta-7-reductase  (DHCR7) gene mapped to 11q12-q13. The result is a defect in cholesterol synthesis.

The clinical features significantly overlap those seen in Meckel (249000) and Joubert (213300) syndromes.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

A high cholesterol diet has been reported to have a beneficial effect on behavior and general well-being.

References
Article Title: 

Cerebrooculofacioskeletal Syndrome

Clinical Characteristics
Ocular Features: 

Congenital cataracts and microphthalmia are frequent findings in this disorder.  Delayed mental development and early death in childhood have limited full delineation of the ocular phenotype.  Photosensitivity, nystagmus, optic nerve atrophy, and pigmentary retinopathy have been reported.  The eyes may appear deeply-set.

Systemic Features: 

Microcephaly, flexion contractures, prominent nasal root and an overhanging upper lip are common features.  Severe developmental and growth delays are evident early followed by progressive behavioral and intellectual deterioration.  Both hypotonia and hyperreflexia have been described.    Kyphosis and scoliosis are common.  CT scans may show intracranial calcifications and brain histology shows severe neurodegeneration with neuronal loss and gliosis.  Respiratory distress may also occur and some individuals have died in the first decade of life.

Genetics

Homozygous mutations in the ERCC6 gene (10q11) seem to be responsible for this autosomal recessive disorder.  Several sets of parents have been consanguineous.  Mutations in the same gene are responsible for Cockayne type B syndrome (133540) and some suggest that the variable phenotype represents a spectrum of disease rather than individual entities. Cerebrooculofacioskeletal syndrome represents the more severe phenotype in this spectrum.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for this disorder.

References
Article Title: 

Homocystinuria, MTHFR Deficiency

Clinical Characteristics
Ocular Features: 

The ocular signs in MTHFR deficiency are likely similar to those found in beta-synthase deficiency (236200) but no comparative study has been reported.  Ectopia lentis is common and the high mobility of the lens carries a significant risk of pupillary block glaucoma and migration into the anterior chamber.

Systemic Features: 

There is a wide range in clinical disease in MTHFR deficiency but the neurological signs and the progressive of disease seem to be more aggressive than in beta-synthase deficiency (236200) . Neonates may have seizures and failure to thrive but other affected patients may live to adulthood without symptoms.  Early death from neurological complications is more common and the mental retardation is apparently more severe.  There is a serious risk for thromboembolic events which may be life-threatening.  Hyperhomocyteinemia and low plasma methionine are present as is increased homocystine in urine.

Genetics

Mutations in MTHFR (1p36.3) are responsible for this form of homocystinuria.  Another form, beta-synthase deficiency (236200), is caused by a mutation in the CBS  gene (21q22.3).  This is an autosomal recessive disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Administration of betaine has been reported to reduce the neurological disease but it must be started early before brain damage occurs.  It does not correct hyperhomocysteinemia nor does it correct CNS MTHFR deficiency.  It has also been reported that betaine in combination with folic acid and cobalamin can prevent symptoms.

References
Article Title: 

Mutation Update and Review of Severe MTHFR

Froese DS, Huemer M, Suormala T, Burda P, Coelho D, Gueant JL, Landolt MA,
Kozich V, Fowler B, Baumgartner MR. Mutation Update and Review of Severe MTHFR
Deficiency. Hum Mutat. 2016 Feb 13.

PubMed ID: 
2687264

Pages

Subscribe to RSS - hypotonia