autosomal recessive

Ataxia with Oculomotor Apraxia 2

Clinical Characteristics
Ocular Features: 

Patients with this disorder have difficulty initiating voluntary ocular movements upon command or following targets (oculomotor apraxia).  This feature is not as prominent or frequent in AOA2 (56%) as it is in ataxia with oculomotor apraxia 1 (208920).  Gaze changes are often initiated first by head thrusting, followed by saccadic eye movements. One may test for this by holding the head whereupon the patient is unable to move the eyes.  Strabismus and nystagmus are present in a significant proportion of patients.  Optokinetic nystagmus is impaired.

Systemic Features: 

Initial development proceeds normally but cerebellar ataxia with significant gait problems appear toward the end of the first decade of life and sometimes not until the third decade (mean age of onset 15 years).   Distal muscle weakness and atrophy are often seen.  Mental decline has been observed in a few individuals but does not occur until midlife.  Sensorimotor deficits are present in many patients.  Tremors, dystonia, and choreiform movements are sometimes seen.  Many patients become wheelchair-bound by the 4th decade of life.

Cerebellar atrophy is revealed by MRI.  Serum alpha-fetoprotein concentrations are usually elevated while serum creatine kinase is increased in some patients.  Circulating cholesterol may also be above normal.  Mild serum changes in these components may be seen in heterozygotes.  Hypoalbuminemia is not present in AOA2.

Genetics

Homozygous mutations in SETX (9q34.13) are responsible for this disorder. 

Ataxia with oculomotor apraxia 2 is distinguished from ataxia-telangiectasia (208900) by the lack of telangiectases and immunological deficiencies. It differs from ataxia with oculomotor apraxia 1 (208920) in having a somewhat later onset, somewhat slower course, and milder oculopraxic manifestations. Cogan-type oculomotor apraxia (257550) lacks other neurologic signs. Oculomotor apraxia may be the presenting sign in Gaucher disease (230800, 230900, 231000).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no beneficial treatment for the neurological disease but physical therapy, speech therapy, and sometimes special education can be helpful.

References
Article Title: 

Epidemiological, clinical, paraclinical and molecular study of a cohort of 102 patients affected with autosomal recessive progressive cerebellar ataxia from Alsace, Eastern France: implications for clinical management

Anheim M, Fleury M, Monga B, Laugel V, Chaigne D, Rodier G, Ginglinger E, Boulay C, Courtois S, Drouot N, Fritsch M, Delaunoy JP, Stoppa-Lyonnet D, Tranchant C, Koenig M. Epidemiological, clinical, paraclinical and molecular study of a cohort of 102 patients affected with autosomal recessive progressive cerebellar ataxia from Alsace, Eastern France: implications for clinical management. Neurogenetics. 2010 Feb;11(1):1-12.

PubMed ID: 
19440741

Ataxia with oculomotor apraxia type 2: a clinical, pathologic, and genetic study

Criscuolo C, Chessa L, Di Giandomenico S, Mancini P, Sacc?+ F, Grieco GS, Piane M, Barbieri F, De Michele G, Banfi S, Pierelli F, Rizzuto N, Santorelli FM, Gallosti L, Filla A, Casali C. Ataxia with oculomotor apraxia type 2: a clinical, pathologic, and genetic study. Neurology. 2006 Apr 25;66(8):1207-10.

PubMed ID: 
16636238

Cataracts, Congenital, Autosomal Recessive 4

Clinical Characteristics
Ocular Features: 

This type of cataract has been reported in a single consanguineous family in which 4 sibs (2 males and 2 females) were diagnosed with cataracts shortly after birth.  Open angle glaucoma developed in two individuals at the age of 7 and 8 years.  The lens opacification involves primarily the posterior subcapsular area.  No genital abnormalities were found in this family.

Another unrelated individual developed progressive cataracts from the age of 2 years.  At cataract surgery it was noted that the posterior capsules were abnormal with thinning of one and a frank lenticonus in the other.

Systemic Features: 

Hypospadias was present in an unrelated male with an inversion of chromosome 9 involving at least two genes.

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in the TDRD7 gene (9p22.33).  Normal function of the gene in vertebrates is required for posttranscriptional control of mRNAs critical to normal lens development.

The single unrelated individual with cataracts and hypospadias had an inversion (inv(9)(q22.33q34.11). One of the two breakpoints (9q34.11) involved the gene NR5A1 which is essential for sexual differentiation.  The ocular and genital phenotypes therefore are likely independent. 

The Tdrd7 gene is expressed in lens fibers and its malfunction causes cataracts in mice.  The evolution of lens opacification in mice closely resembles that observed in the reported patient with cataracts and hypospadias.  Some mutant mice develop open angle glaucoma complete with optic atrophy and nerve cupping.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cataract surgery may be indicated and patients should be monitored and treated for glaucoma.

References
Article Title: 

Mutations in the RNA granule component TDRD7 cause cataract and glaucoma

Lachke SA, Alkuraya FS, Kneeland SC, Ohn T, Aboukhalil A, Howell GR, Saadi I, Cavallesco R, Yue Y, Tsai AC, Nair KS, Cosma MI, Smith RS, Hodges E, Alfadhli SM, Al-Hajeri A, Shamseldin HE, Behbehani A, Hannon GJ, Bulyk ML, Drack AV, Anderson PJ, John SW, Maas RL. Mutations in the RNA granule component TDRD7 cause cataract and glaucoma. Science. 2011 Mar 25;331(6024):1571-6.

PubMed ID: 
21436445

Sengers Syndrome

Clinical Characteristics
Ocular Features: 

This is a mitochondrial DNA depletion syndrome in which congenital cataracts are the hallmark ocular feature.  The bilateral lens opacification is usually total at birth or within the first few weeks of life as manifested by leucocoria. Lens extraction is necessary within the first 6 months of life but visual rehabilitation is nearly always compromised postoperatively by nystagmus and strabismus.  In one series only one eye recovered to 20/40 but the average postoperative acuity was in the range of 20/200 and virtually all students require special education in schools for the visually impaired.  Axial myopia is common with most patients having myopic fundus changes and requiring less than +10 diopters of aphakic correction.  Pale optic disks and a pigmentary retinopathy were noted among 8 of 18 eyes in one series.  Mild and inconsistent dyschromatopsia has been reported in a few patients.  The ERG sometimes shows diminished rod and cone function.

Systemic Features: 

Hypertrophic cardiomyopathy is often diagnosed within a fews days after birth but 40% may escape detection until the second or third decade of life.  It is usually progressive and often fatal in the neonatal period.  Myopathy involves both cardiac and skeletal muscles.  Generalized hypotonia, exercise intolerance, and delayed motor development are important features in the majority of patients.  Metabolic lactic acidosis occurs with relatively minimal excercise.  Skeletal muscle biopsies show ragged-red fibers with combined deficiencies of mitochondrial complexes I, III, and IV along with severe depletion of mtDNA.  Increased urine levels of 3-methylglutaconic have been reported.

The central nervous system is usually not involved and mental development is normal if lactic acidosis is controlled.  However, several children with mental retardation have been reported.

Genetics

Homozygous or compound heterozygous mutations in AGK (7p34), a lipid metabolism gene, are responsible for this condition.  There is considerable variation in the severeity of the phenotypic features but no ocular or cardiac disease has been found in heterozygotes. 

The same gene was found to be mutated in an autosomal recessive congenital cataract (614691) in a single reported sibship. Thorough systemic evaluation found no evidence of cardiac and skeletal muscle disease.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Surgical removal of cataracts may be indicated.

References
Article Title: 

Lack of the mitochondrial protein acylglycerol kinase causes Sengers syndrome

Mayr JA, Haack TB, Graf E, Zimmermann FA, Wieland T, Haberberger B, Superti-Furga A, Kirschner J, Steinmann B, Baumgartner MR, Moroni I, Lamantea E, Zeviani M, Rodenburg RJ, Smeitink J, Strom TM, Meitinger T, Sperl W, Prokisch H. Lack of the mitochondrial protein acylglycerol kinase causes Sengers syndrome. Am J Hum Genet. 2012 Feb 10;90(2):314-20.

PubMed ID: 
22284826

Cataracts, Congenital, Autosomal Recessive 5

Clinical Characteristics
Ocular Features: 

This type of autosomal recessive congenital cataract has been identified in a single consanguineous family.  The lens opacities (not further characterized) are the only ocular abnormalities found in two boys and 1 girl belonging to a single sibship born to parent who were second cousins.  Extensive systemic evaluations found no evidence of clinical disease as found in Sengers syndrome (212350).

Systemic Features: 

There are no systemic abnormalities.

Genetics

This type of cataract results from homozygous mutations in AGK (7q33-q36.1), a lipid metabolism gene.  Sengers syndrome (212350) is also caused by mutations in the same gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cataract surgery may be indicated if the opacities are visually significant..

References
Article Title: 

Retinitis Punctata Albescens

Clinical Characteristics
Ocular Features: 

Uniform white dots are symmetrically distributed in the midportion and periphery of the retina but the central portion of the macula is usually relatively spared in early stages of the disease.  These flecks are present in the first decade of life increasing in density and covering larger areas of the retina in older individuals.  Difficulties with night vision are also noted early and visual acuity may be compromised, in the range of 20/40.  By the fifth and sixth decades there may be retinal pigment atrophy in the midperiphery and this eventually progresses to geographic atrophy of the macular RPE as the visual field becomes more constricted.  The fundus in older individuals resembles that seen in retinitis pigmentosa with retinal vascular attenuation, frank bone spicule pigmentation, macular disease, and pallor of the optic nerves with significant loss of vision.  The ERG shows reduction in scotopic responses and mild reductions in photopic amplitudes.

This form of flecked retina is sometimes considered to be a variant of fundus albipunctatus (136880).  In favor of this argument are the observations in families in which some young members have the fundus picture of fundus albipunctatus (136880) while older ones with more advanced disease have all of the features of retinitis punctata albescens.  Also supportive is the fact that mutations in RLBP1 have been identified in both conditions.  

However, many individuals with fundus albipunctatus (136880) are described as having a stable disease with night blindness as the major symptom while many patients reported with retinitis albescens clearly have a more progressive and more serious disease with a fundus picture in late stages resembling retinitis pigmentosa.  The relationship of these two conditions should become clearer once we learn more about the natural history of these rare disorders.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

This is an autosomal recessive disorder resulting from homozygous or compound heterozygous mutations in RLBP1 (15q26.1).  Parental consanguinity is frequently present.  Mutations in the same gene are also responsible for Bothnia type retinal dystrophy (607475), fundus albipunctatus (136880), and occasional patients with classical retinitis pigmentosa. 

Some authors consider retinitis punctata albescens to have an autosomal dominant pattern of transmission, perhaps based on the presence of white spots in the retina of parents.  However, heterozygotes are always asymptomatic.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

Novel mutations in the cellular retinaldehyde-binding protein gene (RLBP1) associated with retinitis punctata albescens: evidence of interfamilial genetic heterogeneity and fundus changes in heterozygotes

Fishman GA, Roberts MF, Derlacki DJ, Grimsby JL, Yamamoto H, Sharon D, Nishiguchi KM, Dryja TP. Novel mutations in the cellular retinaldehyde-binding protein gene (RLBP1) associated with retinitis punctata albescens: evidence of interfamilial genetic heterogeneity and fundus changes in heterozygotes. Arch Ophthalmol. 2004 Jan;122(1):70-5.

PubMed ID: 
14718298

Fleck Retina, Benign Familial

Clinical Characteristics
Ocular Features: 

The appearance of the retina is said to be distinctive.  Bright, discrete yellow-white dots or fish-tail flecks are seen extending from the parafoveal region to the periphery where they may be larger and more confluent.  The central macula is spared.  The flecks autofluoresce and fluorescein angiography reveals mild irregular hyperfluorescence.  These have been described in multiple asymptomatic patients during the first decade of life and might be congenital in origin.  Photopic and scotopic vision remains normal and no ERG or EOG abnormalities can be recorded. The retinal pigment epithelium and vasculature are normal.

Systemic Features: 

No systemic disease is present.

Genetics

This is an autosomal recessive disorder resulting from homozygous or compound heterozygous mutations in the PLA2G5 gene located at 1p36.13-p36.12.

Retinal flecks can be seen in a number of hereditary retinal syndromes (see FLecked Retina Syndromes).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is necessary.

References
Article Title: 

Flecked-retina syndromes

Walia S, Fishman GA, Kapur R. Flecked-retina syndromes. Ophthalmic Genet. 2009 Jun;30(2):69-75..

PubMed ID: 
19373677

Spastic Paraplegia 15

Clinical Characteristics
Ocular Features: 

Yellowish flecks resembling those seen in fundus flavimaculatus are present, primarily in the macular area.   These can be present in large numbers in homozygotes with the full neurological syndrome.  Background retinal pigmentation appears clinically normal but fluorescein angiography shows a strikingly mottled picture with areas of hyper- and hypofluorescence.  Retinal flecks have also been reported in heterozygous parents.

The central macula exhibits autofluorescence.  Standard EOG and ERG recordings are normal but multifocal electroretinography shows subnormal responses in the macular area.  Visual acuity is minimally impacted.

Systemic Features: 

This is a form of spastic paraplegia with progressive spasticity primarily affecting the lower limbs.  Mental retardation (or at least cognitive impairment), dysarthria, a thin corpus callosum, and distal amyotrophy are often present.  Hearing deficits have also been described.  Some but not all patients have tremors, cerebellar ataxia, epilepsy and behavioral disturbances. Onset is between 10 and 19 years of age.  Little is known about the rate of symptom progression.

Genetics

This is an autosomal recessive disorder resulting from mutations in the ZFYVE26 gene (14q24.1).

Spastic paraplegia 7 (607259) has similar neurological features but with ptosis, optic atrophy, and nystagmus.  Congenital cataracts occur in addition to the neurological signs in spastic paraplegia 46 (614409) .

Other disorders with retinal flecks are described in Flecked Retina Syndromes.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Fleck retina in Kjellin's syndrome

Farmer SG, Longstreth WT Jr, Kalina RE, Todorov AB. Fleck retina in Kjellin's syndrome. Am J Ophthalmol. 1985 Jan 15;99(1):45-50.

PubMed ID: 
3966518

Canavan Disease

Clinical Characteristics
Ocular Features: 

Optic atrophy is the primary and perhaps only ocular manifestation of Canavan disease.  Acuity levels have not been reported but it has been noted that some infants and young children with early onset severe disease are able to track targets.  The ocular phenotype has not been well delineated.

Systemic Features: 

The clinical diagnosis of Canavan disease is suggested when the triad of hypotonia, macrocephaly and head lag is present.  It is a progressive form of spongy degeneration of the central nervous system but its onset, course, and severity are variable.

The disease is often evident before 6 months of age and survival is limited to a few months or years in infants with such early onset.  Such patients have the most severe and rapidly progressive disease.  It is noteworthy that, even though such infants do not achieve normal milestones such as sitting and standing, they do often interact socially by laughing, smiling, and reaching for objects.  Most young children are quiet and apathetic but some become irritable and develop spasticity as they grow.  CNS damage is evident as leukodystrophy on neuroimaging studies but this may not be present in later onset, milder forms of the disease.         

Other individuals may have a later and milder juvenile onset of symptoms and may present with delayed speech or motor development late in the first decade.  They often attend regular school but may benefit from tutoring and speech therapy.  They may live to adolescence or early adulthood.  Maldevelopment of the organ of Corti is responsible for hearing deficits in some children.

Genetics

Canavan disease is an autosomal recessive disorder resulting from homozygous or compound heterozygous mutations in the gene (ASPA) located at 17p13.2 encoding the enzyme aspartoacylase.  N-acetylaspartic acid (NAA) levels are usually elevated in urine.  However, because the levels of NAA can vary depending on the severity of clinical disease, gene testing provides a more reliable diagnosis. 

The carrier frequency is high among members of the Ashkenazi Jewish population.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Antiepileptic drugs can be helpful.  Augmented feeding (gastric tubes)may be needed to maintain nutrition, while physical therapy and exercise may prevent contractures.  Speech therapy and low vision aids might be of benefit. Rare patients with a hearing deficit should be evaluated for possible benefit of hearing aids.

References
Article Title: 

Fundus Albipunctatus

Clinical Characteristics
Ocular Features: 

This disorder is often considered to belong to the category of retinal disease known as flecked retina syndrome.  Further, the nomenclature is not standardized and varying names have been attached to the more or less characteristic fundus picture consisting of uniformly distributed small yellow-white dots in the retina.  These tend to be concentrated in the midperiphery.  The macula usually is not involved in young people although ERG evidence suggests some worsening of cone dysfunction with age and central acuity may be decreased in midlife.  Frank macular degeneration has been seen clinically .  Delayed dark adaptation can be demonstrated with delays in recovery of rod and cone function.  Patients complain of night blindness beginning in childhood with little evidence of progression.

The disease known as retinitis punctata albescens (136880) may or may not be a unique disorder.  It is sometimes grouped with fundus albipunctatus while others consider it to be a separate entity.  Evidence for its uniqueness is based on the progressive nature of field loss and the presence of pigmentary changes and retinal vascular attenuation which are not found in fundus albipunctatus.  Further, the scotopic ERG waveforms usually do not regenerate.  More discriminating studies, especially genotyping, will likely provide additional information.  It would also be useful to have additional follow-up information on families. 

Systemic Features: 

No systemic disease is associated.

Genetics

Fundus albipunctatus is a genetically heterogeneous disorder.  Mutations in two genes, PRPH2 (6p21.1) and RDH5 (12q13.2) have been found among families.  The inheritance pattern for families with mutations in PRPH2 is consistent with autosomal dominant inheritance while mutations in RDH5 result in an autosomal recessive pattern.  Mutations in RLBP1 have also been found in some families.

Gene studies so far have not been helpful in discriminating between fundus albipunctatus and retinitis punctata albescens (136880).  For example, RLBP1 mutations have been identified among members of the same kindred having the clinical diagnosis of retinitis punctata albescens (136880) among older individuals while younger patients had features of fundus albipunctatus.  Further, the latter disorder has also been described among families with mutations in PRPH2 and RHO hinting at further genetic heterogeneity.

A similar clinical picture may be seen in Bietti crystalline corneoretinopathy (210370), Bardet-Biedl syndrome (209900), and hyperoxaluria (259900).  More information on flecked retina syndromes may be found at Flecked Retina Syndromes.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available to restore full receptor cell function.  However, high oral doses of beta-carotene may lead to an improvement in night blindness. Low vision aids could be beneficial when central acuity is damaged.

References
Article Title: 

Persistent Hyperplastic Primary Vitreous

Clinical Characteristics
Ocular Features: 

Persistence and hyperplasia of the embryonic vitreous in most individuals results in significant ocular morbidity.  It results from a transcription factor deficiency in retinal ganglion cells which in turn negatively impacts development of the retinal vasculature.  As a consequence, the fetal hyaloid vasculature fails to regress and its persistence leads to a retrolental mass.

PHPV usually occurs unilaterally and affected eyes are generally blind from birth. Leukocoria secondary to the presence of a retrolental fibrovascular stalk is easily visible.  Nystagmus is frequently present and some patients have microphthalmos. The anterior segment may also be involved as evidenced by the presence of peripheral anterior synechiae, corneal opacities, cataracts, and glaucoma.  Contracture of the retrolental tissue In the posterior chamber results in the ciliary processes being pulled centrally and can lead to hemorrhage and retinal detachment. 

The clinical manifestations can make it difficult to distinguish from Norrie disease.

Systemic Features: 

No consistent systemic signs have been reported in PHPV individuals.

Genetics

The majority of PHPV cases occur sporadically, but families with transmission patterns compatible with both autosomal recessive and autosomal dominant patterns have been reported.

A six-generation family has been reported in which affected members had homozygous mutations in ATOH7 (10q21.3).  Based on mouse studies, this gene is expressed in the developing optic cup at the time that coincides with retinal ganglion cell formation.  Mice with absence of functioning Atoh7 lack retinal ganglion cells and optic nerves and develop PHPV.

A single family with presumed bilateral PHPV in 3 generations in a pattern consistent with autosomal dominant inheritance has been reported (611308).  However, no genotyping was reported and only the proband and his father had ophthalmologic examinations.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No medical or surgical treatment is effective.  The majority of individuals have no light perception.

References
Article Title: 

Pages

Subscribe to RSS - autosomal recessive