autosomal recessive

Fructose Intolerance

Clinical Characteristics
Ocular Features: 

Dense cataracts have been reported in the first decade of life in several patients.

Systemic Features: 

Abdominal pain, vomiting and hypoglycemia usually appears in infancy upon the introduction of fructose or sucrose to the diet.  Some infants have a more severe reaction to such sugars with lethargy, seizures and coma.  Older children and adults develop a protective aversion to fruits and sweets.  Chronic ingestion leads to liver cirrhosis, renal tubule damage, growth retardation, and even malnutrition.  Adults may also have hypoglycemia and metabolic acidosis when challenged with sucrose and fructose.

Genetics

This is an autosomal recessive disorder resulting from mutations in the ALDOB gene (9q31.1).  However, several heterozygous patients with symptoms have been reported and such individuals may be predisposed to hyperuricemia.  Multiple mutations have been identified in the ALDOB gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment with a fructose restricted diet is highly effective but must be strictly enforced to allow normal growth.

References
Article Title: 

Hereditary fructose intolerance

Ali M, Rellos P, Cox TM. Hereditary fructose intolerance. J Med Genet. 1998 May;35(5):353-65. Review.

PubMed ID: 
9610797

Retinitis Pigmentosa, Hearing Loss, Ataxia, Cataract, and Polyneuropathy

Clinical Characteristics
Ocular Features: 

Cataracts and a pigmentary retinopathy occur in this condition but only in some, primarily older, patients.  The lens opacities progress and may become visually significant by the third decade.  Bone-spicule-shaped pigment clumping may be present in the midperiphery while the optic disk is often pale and the retinal vessels are attenuated. The ERG responses are consistent with a rod-cone dystrophy.

Systemic Features: 

This is a progressive neurological disorder with onset of signs and symptoms in childhood although full expression may not occur until adulthood.  Young children can have hyporeflexia, pes cavus, spasticity, and gait ataxia.  A sensorineural hearing loss may also be present in childhood but sometimes not until later.  Hyperreflexia with extensor plantar responses and Achilles tendon contractures are often present later.  The peripheral polyneuropathy is predominantly demyelinating with both sensory and motor components and is present in all adults.  Cerebellar atrophy, primarily in the vermis, can be demonstrated on MRI examination.  Mental function is usually not impaired. Some patients have dysarthria. 

This disorder has some clinical similarities to Refsum disease (266500).

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in the ABHD12 gene (20p11.21).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is directed at symptoms.  Visually significant cataracts may require removal.  Low vision aids and physical therapy can be helpful.

References
Article Title: 

Mutations in ABHD12 cause the neurodegenerative disease PHARC: An inborn error of endocannabinoid metabolism

Fiskerstrand T, H'mida-Ben Brahim D, Johansson S, M'zahem A, Haukanes BI, Drouot N, Zimmermann J, Cole AJ, Vedeler C, Bredrup C, Assoum M, Tazir M, Klockgether T, Hamri A, Steen VM, Boman H, Bindoff LA, Koenig M, Knappskog PM. Mutations in ABHD12 cause the neurodegenerative disease PHARC: An inborn error of endocannabinoid metabolism. Am J Hum Genet. 2010 Sep 10;87(3):410-7.

PubMed ID: 
20797687

Spastic Paraplegia 7

Clinical Characteristics
Ocular Features: 

Many but not all individuals have significant visual loss due to optic atrophy.  Other ocular signs include supranuclear palsy, ptosis, and nystagmus.  Older individuals with advanced disease may have progressive external ophthalmoplegia.

Systemic Features: 

There is a great deal of clinical heterogeneity between families and not all individuals have severe neurological disease.  Progressive neurological signs (primarily abnormal gait) are often present in late childhood or early adolescence but may occur late in life.  Clinical features include muscle atrophy and weakness with spasticity (more pronounced in the lower limbs), ataxia, pyramidal signs, dysphagia, and cerebellar dysarthria.  Hyperreflexia and extensor plantar responses are often present.  Cognitive deficits are manifest as deficits in attention and higher levels of reasoning.  Some patients have a mild peripheral neuropathy with decreased vibratory sense.  Many patients have significant dysfunction of the bladder sphincter.  Adults may lose their mobility and are confined to a wheelchair.

Some patients develop scoliosis and pes cavus.  The MRI often shows cerebellar and mild frontal cortical atrophy.

Genetics

This type of spastic paraplegia results from mutations in the paraplegin gene, SPG7 (16q24.3).  It is usually transmitted in an autosomal recessive pattern although heterozygous patients with symptoms have been reported. Evidence suggests that the symptoms arise from a defect in mitochondrial respiration.

Patients with spastic paraplegia 15 (270700) have a similar neurological phenotype plus a flecked retina.  Congenital cataracts are part of the phenotype of spastic paraplegia 46 (614409).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is symptomatic.  Physical, speech, and occupational therapy may be helpful in selected patients.  Low vision aids may be of benefit in some individuals, at least early in the disease.

References
Article Title: 

Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance

Pfeffer G, Gorman GS, Griffin H, Kurzawa-Akanbi M, Blakely EL, Wilson I, Sitarz K, Moore D, Murphy JL, Alston CL, Pyle A, Coxhead J, Payne B, Gorrie GH, Longman C, Hadjivassiliou M, McConville J, Dick D, Imam I, Hilton D, Norwood F, Baker MR, Jaiser SR, Yu-Wai-Man P, Farrell M, McCarthy A, Lynch T, McFarland R, Schaefer AM, Turnbull DM, Horvath R, Taylor RW, Chinnery PF. Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance. Brain. 2014 Apr 10. [Epub ahead of print].

PubMed ID: 
24727571

A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary spastic paraplegia

Arnoldi A, Tonelli A, Crippa F, Villani G, Pacelli C, Sironi M, Pozzoli U, D'Angelo MG, Meola G, Martinuzzi A, Crimella C, Redaelli F, Panzeri C, Renieri A, Comi GP, Turconi AC, Bresolin N, Bassi MT. A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary spastic paraplegia. Hum Mutat. 2008 Apr;29(4):522-31.

PubMed ID: 
18200586

Congenital Disorder of Glycosylation, Type Ia

Clinical Characteristics
Ocular Features: 

Strabismus, roving eye movements (and nystagmus), and visual inattention are found in nearly all patients. Esotropia with defective abduction seems to be the most common oculomotor finding and may be present at birth.  Cataracts, ocular colobomas, oculomotor apraxia, disc pallor, and glaucoma have also been reported.  Vision is always subnormal. Reports of ocular disease before modern genotyping are not specific to the subtypes of CDG I now recognized.

This is a congenital, progressive disorder of photoreceptor degeneration with a later onset of progressive pigmentary retinopathy.  It is described in some cases as a typical retinitis pigmentosa.  The ERG is abnormal in all patients even if the pigmentary pattern is atypical for RP.  Rod responses are usually absent while the cone b-wave implicit time is delayed.  The degree of photoreceptor damage is variable, however.  Extended retinal function among younger patients suggest that the ‘on-pathway’ evolving synapses in the outer plexiform layer among photoreceptors, bipolar cells, and horizontal cells is severely dysfunctional.

Systemic Features: 

This is a multisystem disorder, often diagnosed in the neonatal period by the presence of severe encephalopathy with hypotonia, hyporeflexia, and poor feeding.  Failure to thrive, marked psychomotor retardation, delayed development, growth retardation, and ataxia become evident later in those who survive.  Cerebellar and brainstem atrophy with a peripheral neuropathy can be demonstrated during late childhood.  Some older patients have a milder disease, often with muscle atrophy and skeletal deformities such as kyphoscoliosis and a fusiform appearance of the digits.  Maldistribution of subcutaneous tissue is often seen resulting in some dysmorphism, especially of the face.  Hypogonadism and enlargement of the labia majora are commonly present.  Some patients have evidence of hepatic and cardiac dysfunction which together with severe infections are responsible for a 20% mortality rate in the first year of life.

Genetics

This is one of a group of genetically (and clinically) heterogeneous autosomal recessive conditions caused by gene mutations that result in enzymatic defects in the synthesis and processing of oligosaccharides onto glycoproteins. This type (Ia) is the most common.   The mutation lies in the PMM2 gene (16p13.2).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Most children require tube feeding with nutritional supplements.  The risk of systemic infections is high.  Those patients who survive into the second decade and beyond may require orthopedic procedures and are confined to wheelchairs.  Physical, occupational, and speech therapy along with parental support are important.

References
Article Title: 

Congenital Disorder of Glycosylation, Type Iq

Clinical Characteristics
Ocular Features: 

Colobomas (iris, choroid, and sometimes optic nerve), optic nerve hypoplasia and nystagmus have been reported.  Visual acuity is variable depending upon the degree of nerve hypoplasia. The eyebrows may be highly arched, while downward slanting lid fissures, and hypertelorism may also be present.

Congenital cataracts, glaucoma and microphthalmia have been reported in several individuals.

Systemic Features: 

Onset of symptoms commonly begins in infancy with severe hypotonia while developmental delays soon become evident as most children do not achieve normal milestones.  The amount of cognitive impairment is variable.  Congenital cardiac defects, ichthyosis, and hypertrichosis may be present.  The skin over the dorsum of the hands and feet often appears dark.  Ataxia is sometimes present and MRIs may reveal vermal and cerebellar hypoplasia.

Facial dysmorphism is common.  Low-set malformed ears, low hairline, depressed nasal bridge, redundant facial skin, decreased subcutaneous tissue, large mouth, thin lips, and long face have been noted.

There is considerable variation in clinical manifestations and longevity varies from infancy to adulthood.

Genetics

This glycosylation disorder is one of a number of rare hepatic/intestinal disorders caused by a deficiency in N-oligosaccharide synthesis.  It is inherited in an autosomal recessive pattern as a result of mutations in SRD5A3 (4q12).  Both homozygous and compound heterozygous genotypes have been reported.  It is allelic to Kahrizi syndrome (612713) with a number of overlapping features including ocular colobomas and cognitive deficiencies.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

The administration of caloric supplements through tube feeding may be required to maintain adequate nutrition.Orthopedic deformities can sometimes be corrected surgically.

References
Article Title: 

A novel cerebello-ocular syndrome with abnormal glycosylation due to abnormalities in dolichol metabolism

Morava E, Wevers RA, Cantagrel V, Hoefsloot LH, Al-Gazali L, Schoots J, van Rooij A, Huijben K, van Ravenswaaij-Arts CM, Jongmans MC, Sykut-Cegielska J, Hoffmann GF, Bluemel P, Adamowicz M, van Reeuwijk J, Ng BG, Bergman JE, van Bokhoven H, Korner C, Babovic-Vuksanovic D, Willemsen MA, Gleeson JG, Lehle L, de Brouwer AP, Lefeber DJ. A novel cerebello-ocular syndrome with abnormal glycosylation due to abnormalities in dolichol metabolism. Brain. 2010 Nov;133(11):3210-20.

PubMed ID: 
20852264

SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder

Cantagrel V, Lefeber DJ, Ng BG, Guan Z, Silhavy JL, Bielas SL, Lehle L, Hombauer H, Adamowicz M, Swiezewska E, De Brouwer AP, Bl?omel P, Sykut-Cegielska J, Houliston S, Swistun D, Ali BR, Dobyns WB, Babovic-Vuksanovic D, van Bokhoven H, Wevers RA, Raetz CR, Freeze HH, Morava E, Al-Gazali L, Gleeson JG. SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder. Cell. 2010 Jul 23;142(2):203-17.

PubMed ID: 
20637498

Cataracts, Congenital Nuclear

Clinical Characteristics
Ocular Features: 

Congenital nuclear cataracts are the only ocular abnormalities in these conditions.  There may be some cortical opacifications as well.  The nuclear opacifications may not be sufficiently dense in some patients to require cataract surgery.  Nothing is known of their natural history, however.

Systemic Features: 

No systemic disease is associated with these congenital cataracts.

Genetics

All three of these nuclear cataracts are inherited in autosomal recessive patterns.  They have been reported in rare families in which the parents were consanguineous.

CATCN1 was reported in a 4-generation Pakistani family having an unknown mutation localized to 19q13.

Another congenital nuclear cataract (CATCN2) results from mutations in the CRYBB3 (22q11.23) gene reported in 2 consanguineous Pakistani families.

CATCN 3 results from mutations in CRYBB1 (22q12.1) as reported in two consanguineous Israeli Bedouin families with 14 affected individuals.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Surgical removal may be indicated if the lens opacities are visually significant.  Vision may be sufficiently impaired in some children that surgery is required before 2 years of age.

References
Article Title: 

Kahrizi Syndrome

Clinical Characteristics
Ocular Features: 

In an Iranian family with 3 affected sibs, cataracts (not further characterized) were noted in late adolescence.  Iris colobomas, unilateral in one sib and bilateral in another, were present.

Systemic Features: 

Children have severe psychomotor delays from birth and have severe mental retardation.  Speech and normal motor function never develop fully.  Thoracic kyphosis begins in late childhood and contractures develop in the elbows and knees.  A CAT scan in one patient revealed only normal findings.  Facial features have been described as ‘coarse’ with prominent lips, broad nasal bridge, and a bulbous nose.  Some individuals with this condition have lived into the 5th decade.  Ataxia is usually present although the cerebellum may be normal on MRI.

Genetics

This is an autosomal recessive condition resulting from homozygous mutations in the SRD5A3 gene (4q12).

Kahrizi syndrome is allelic to CDG1Q, or congenital disorder of glycosylation type Iq (612379), an autosomal recessive disorder with mutations in the same gene and a partially overlapping ocular phenotype.

At least 10 families have been reported with mutations in this gene considered important to glycosylation.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No specific treatment is available for this condition although physical therapy and cataract surgery might be considered in specific individuals.

References
Article Title: 

SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder

Cantagrel V, Lefeber DJ, Ng BG, Guan Z, Silhavy JL, Bielas SL, Lehle L, Hombauer H, Adamowicz M, Swiezewska E, De Brouwer AP, Bl?omel P, Sykut-Cegielska J, Houliston S, Swistun D, Ali BR, Dobyns WB, Babovic-Vuksanovic D, van Bokhoven H, Wevers RA, Raetz CR, Freeze HH, Morava E, Al-Gazali L, Gleeson JG. SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder. Cell. 2010 Jul 23;142(2):203-17.

PubMed ID: 
20637498

Cataracts, Congenital, Autosomal Recessive 2

Clinical Characteristics
Ocular Features: 

Bilateral nuclear lens opacities are either present at birth or noted during infancy.  The cataracts were sufficiently dense that surgery is necessary within several months of age in most patients.  No other ocular disease is present.

Systemic Features: 

No systemic abnormalities are present.

Genetics

CATC2 is an autosomal recessive condition that has been reported in 12 consanguineous Pakistani families.  Homozygous mutations in FYCO1 (3p21.31) segregated with the lens opacities as expected.  Mutations in FYC01 are among the most common causes of congenital cataracts in Pakistan and may account for about 10% of the total genetic load of cataracts in this country.  Mutations in the same gene have been found segregating in several consanguineous Arab families with congenital cataracts as well.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cataract surgery is frequently necessary during infancy.

References
Article Title: 

Meckel Syndrome

Clinical Characteristics
Ocular Features: 

The ocular phenotype is highly variable.  The globe is often malformed or may be clinically absent.  Cryptophthalmos, clinical anophthalmia, and microphthalmos with sclerocornea and microcornea have been reported.  Posterior staphylomas, retinal dysplasia, partial aniridia, cataracts, and hypoplasia or absence of the optic nerve are sometimes seen.  Some patients have incompletely formed eyes with shallow anterior chambers, angle anomalies, and a persistent tunica vasculosa with lens opacification.  Histopathology may reveal thinning of the nerve fiber layer and a paucity of retinal ganglion cells.  The retina has been described as dysplastic with foci of rosette-like structures and abundant glial cells.

Systemic Features: 

Meckel or Meckel-Gruber syndrome is a clinically and genetically heterogeneous group of disorders with severe multisystem manifestations.  The triad of cystic renal disease, polydactyly (and sometimes syndactyly), and a skull malformation (usually an encephalocele) is considered characteristic of MKS.  However, these signs are variable and only about 60% of patients have all three features.  Many patients have additional signs such as malformations of the biliary tree, cleft palate (and/or lip), sloping forehead, low-set ears, short neck, low-set ears, ambiguous genitalia, and short, bowed limb bones.  Pulmonary hypoplasia is common which, together with kidney and liver disease, is responsible for the poor prognosis of most infants. 

Many clinical abnormalities resemble those present in the Smith-Lemli-Opitz syndrome (270400) and in Joubert syndrome (213300).

Genetics

Most conditions in this group are inherited in an autosomal recessive pattern.  Mutations in 9 genes have been identified as responsible for some variant of MKS in which there is a considerable range of clinical expression.  There is significant clinical overlap with Joubert syndrome and it is not surprising that at least 5 of these mutations have been identified in both conditions.  Further nosological confusion is generated by those who consider patients with the severe, lethal phenotype to have Meckel syndrome while those with milder disease are labeled Joubert syndrome, regardless of genotype.

Rare heterozygotes have been reported with isolated features such as polydactyly.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for this syndrome.  The prognosis for life beyond infancy is poor due to the advanced dysfunction of numerous organs such as the kidney, lungs, liver and the central nervous system.

References
Article Title: 

Clinical and genetic heterogeneity in Meckel syndrome

Paavola P, Salonen R, Baumer A, Schinzel A, Boyd PA, Gould S, Meusburger H, Tenconi R, Barnicoat A, Winter R, Peltonen L. Clinical and genetic heterogeneity in Meckel syndrome. Hum Genet. 1997 Nov;101(1):88-92.

PubMed ID: 
9385376

Majewski Syndrome

Clinical Characteristics
Ocular Features: 

No clinical information is available on the ocular features in this disorder.  The fundi have been described as normal in one patient but postmortem histopathology at 8 weeks revealed optic nerve edema with segmental axonal dropout and loss of myelin.  The nerve fiber layer of the retina was prominent with some proliferation of glial tissue.  Early nuclear sclerosis was also present.

Systemic Features: 

This disorder results from a dysgenesis of the cilia and is one of a group of short rib-polydactyly disorders.  Congenital anomalies are found in multiple organs including heart, lungs, skeleton, intestines, genitalia, pancreas, liver, and kidneys.  The diagnostic characteristic of SRPS type II is extreme shortening of the tibia in addition to short ribs in this type of short-limbed dwarfism.

Midline facial clefting, especially cleft lip, is common.  The epiglottis and lungs are often hypoplastic and the kidneys are polycystic.  Polydactyly and polysyndactyly of both pre- and postaxial types are usually present.  Most neonates with SRPS type II do not live beyond infancy.

Genetics

This is an autosomal recessive condition resulting from homozygous mutations in the NEK1 gene (4q33), or, rarely, from digenic biallelic mutations in NEK1 and DYNC2H1 (11q22.3).

Another condition with some of the same features leading to respiratory distress is asphyxiating thoracic dysplasia 1 (208500), or Jeune syndrome.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available for this condition but surgical treatment could be considered for specific anomalies.

References
Article Title: 

NEK1 mutations cause short-rib polydactyly syndrome type majewski

Thiel C, Kessler K, Giessl A, Dimmler A, Shalev SA, von der Haar S, Zenker M, Zahnleiter D, Stoss H, Beinder E, Abou Jamra R, Ekici AB, Schroder-Kress N, Aigner T, Kirchner T, Reis A, Brandst?SStter JH, Rauch A. NEK1 mutations cause short-rib polydactyly syndrome type majewski. Am J Hum Genet. 2011 Jan 7;88(1):106-14.

PubMed ID: 
21211617

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