autosomal recessive

Muscular Dystrophy, Congenital, with Cataracts and Intellectual Disability

Clinical Characteristics
Ocular Features: 

Cataracts have been diagnosed by 6 months of age and may be congenital in origin. Several patients have had strabismus.

Systemic Features: 

Progressive muscle weakness begins in early childhood.  Hypotonia is usually present at birth followed by atrophy of the proximal muscles (especially in the lower limbs).  Muscle weakness progresses for several years and may stabilize but not before severe gait difficulties occur.  Most adult patients are confined to a wheelchair.  No cardiac involvement occurs although respiratory weakness is often present.  Serum creatine kinase is usually elevated and biopsied muscle fibers show dystrophic changes and increased variability in fiber size with vacuolization.

Other signs in some individuals are contractures, scoliosis, seizures, short stature, cognitive deficits (usually mild), and spinal rigidity.  Paradoxically, some patients have limb spasticity and hyperreflexia with pyramidal signs.  No cerebellar signs are present.

Genetics

This condition results from homozygous or compound heterozygous mutations in the INPP5K gene (17p13).  

See Marinesco-Sjogren Syndrome for a disorder with a somewhat similar clinical presentation plus cerebellar signs.  It is caused by a different mutation, however.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cataracts have been surgically removed in several patients by the age of two years.  Physical therapy may be beneficial.  Selected individuals could benefit from release of contractures.

References
Article Title: 

Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment

Wiessner M, Roos A, Munn CJ, Viswanathan R, Whyte T, Cox D, Schoser B, Sewry C, Roper H, Phadke R, Marini Bettolo C, Barresi R, Charlton R, Bonnemann CG, Abath Neto O, Reed UC, Zanoteli E, Araujo Martins Moreno C, Ertl-Wagner B, Stucka R, De Goede C, Borges da Silva T, Hathazi D, Dell'Aica M, Zahedi RP, Thiele S, Muller J, Kingston H, Muller S, Curtis E, Walter MC, Strom TM, Straub V, Bushby K, Muntoni F, Swan LE, Lochmuller H, Senderek J. Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment. Am J Hum Genet. 2017 Mar 2;100(3):523-536.

PubMed ID: 
28190456

Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy

Osborn DP, Pond HL, Mazaheri N, Dejardin J, Munn CJ, Mushref K, Cauley ES, Moroni I, Pasanisi MB, Sellars EA, Hill RS, Partlow JN, Willaert RK, Bharj J, Malamiri RA, Galehdari H, Shariati G, Maroofian R, Mora M, Swan LE, Voit T, Conti FJ, Jamshidi Y, Manzini MC. Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjogren Syndrome and Dystroglycanopathy. Am J Hum Genet. 2017 Mar 2;100(3):537-545.

PubMed ID: 
28190459

Kufor-Rakeb Syndrome

Clinical Characteristics
Ocular Features: 

Most patients have a supranuclear gaze paresis.  Patients later may have dystonic oculogyric spasms.

Systemic Features: 

This is a rapidly progressive neurodegenerative disorder with juvenile onset.  First signs of Parkinisonism are evident between the ages of 12 and 16 years of age.  Within a year of onset severe motor handicaps develop along with some degree of dementia with aggression and visual hallucinations.  Cognitive decline is often a feature.  Fine tremors in the chin may be seen along with other extrapyramidal signs but these are not prominent in the limbs.  Instead there is often rigidity and bradykinesia.  Dysphagia, dysarthria, and ataxia are features in many patients.  Peripheral sensory neuropathy and anosmia are present in some individuals. 

Brain imaging often reveals generalized atrophy of the cerebellum, cerebral cortex, and brainstem.

Genetics

This condition results from homozygous or compound heterozygous mutations in the ATP13A2 gene (1p36.13).  

Biallelic mutations in the same gene are also responsible for spastic paraplegia 78 (617225) with somewhat similar clinical features except for the general absence of Parkinsonism.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There may be an initial therapeutic response to L-DOPA but this is often not maintained

References
Article Title: 

Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78)

Estrada-Cuzcano A, Martin S, Chamova T, Synofzik M, Timmann D, Holemans T, Andreeva A, Reichbauer J, De Rycke R, Chang DI, van Veen S, Samuel J, Schols L, Poppel T, Mollerup Sorensen D, Asselbergh B, Klein C, Zuchner S, Jordanova A, Vangheluwe P, Tournev I, Schule R. Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78). Brain. 2017 Feb;140(Pt 2):287-305.

PubMed ID: 
28137957

Spastic Paraplegia 78

Clinical Characteristics
Ocular Features: 

Reduced upgaze with nystagmus and strabismus have been reported.  

Systemic Features: 

This progressive neurodegenerative disorder usually has its onset in young adults but the signs and symptoms are highly variable.  Ambulation and gait difficulties combined with spasticity and lower limb weakness are common signs.  Ataxia and dysarthria are also important signs.  Some individuals have dementia while others have only mild cognitive impairment.  Some individuals have mild signs of Parkinsonism.

Brain imaging may show cerebellar and cortical atrophy with a thin corpus callosum. 

Genetics

This condition results from homozygous or compound heterozygous mutations in the ATP13A2 gene (1p36.13).

The same gene is also mutated in the Kufor-Rakeb syndrome (606693), an early-onset form of Parkinsonism.  

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78)

Estrada-Cuzcano A, Martin S, Chamova T, Synofzik M, Timmann D, Holemans T, Andreeva A, Reichbauer J, De Rycke R, Chang DI, van Veen S, Samuel J, Schols L, Poppel T, Mollerup Sorensen D, Asselbergh B, Klein C, Zuchner S, Jordanova A, Vangheluwe P, Tournev I, Schule R. Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78). Brain. 2017 Feb;140(Pt 2):287-305.

PubMed ID: 
28137957

Genetic and phenotypic characterization of complex hereditary spastic paraplegia

Kara E, Tucci A, Manzoni C, Lynch DS, Elpidorou M, Bettencourt C, Chelban V, Manole A, Hamed SA, Haridy NA, Federoff M, Preza E, Hughes D, Pittman A, Jaunmuktane Z, Brandner S, Xiromerisiou G, Wiethoff S, Schottlaender L, Proukakis C, Morris H, Warner T, Bhatia KP, Korlipara LV, Singleton AB, Hardy J, Wood NW, Lewis PA, Houlden H. Genetic and phenotypic characterization of complex hereditary spastic paraplegia. Brain. 2016 Jul;139(Pt 7):1904-18.

PubMed ID: 
27217339

Encephalopathy, Progressive, with Amyotrophy and Optic Atrophy

Clinical Characteristics
Ocular Features: 

Optic atrophy is present.

Systemic Features: 

This is a progressive neurodegenerative condition in which hypotonia and delayed development are evident between birth and 14 months of age.  Developmental milestones, if attained, soon regress accompanied by distal amyotrophy, cognitive impairment that may be severe, ataxia, spastic tetraplegia, dysarthria, and scoliosis.  Seizures often occur.

Brain imaging reveals cerebellar and cerebral atrophy.  Iron accumulation may be seen in the pallidum and substantia nigra.  The corpus callosum appears abnormally thin.  Muscle biopsy shows evidence of denervation atrophy.

Genetics

Homozygous or compound heterozygous mutations in the TBCE gene (1q42.3) can cause this disorder.  

Biallelic mutations in the same gene also cause Kenny-Caffey syndrome type 1 (244460) and a hypoparathyroidism dysmorphism syndrome (241410).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

TBCE Mutations Cause Early-Onset Progressive Encephalopathy with Distal Spinal Muscular Atrophy

Sferra A, Baillat G, Rizza T, Barresi S, Flex E, Tasca G, D'Amico A, Bellacchio E, Ciolfi A, Caputo V, Cecchetti S, Torella A, Zanni G, Diodato D, Piermarini E, Niceta M, Coppola A, Tedeschi E, Martinelli D, Dionisi-Vici C, Nigro V, Dallapiccola B, Compagnucci C, Tartaglia M, Haase G, Bertini E. TBCE Mutations Cause Early-Onset Progressive Encephalopathy with Distal Spinal Muscular Atrophy. Am J Hum Genet. 2016 Oct 6;99(4):974-983.

PubMed ID: 
27666369

Biallelic Mutations in TBCD, Encoding the Tubulin Folding Cofactor D, Perturb Microtubule Dynamics and Cause Early-Onset Encephalopathy

Flex E, Niceta M, Cecchetti S, Thiffault I, Au MG, Capuano A, Piermarini E, Ivanova AA, Francis JW, Chillemi G, Chandramouli B, Carpentieri G, Haaxma CA, Ciolfi A, Pizzi S, Douglas GV, Levine K, Sferra A, Dentici ML, Pfundt RR, Le Pichon JB, Farrow E, Baas F, Piemonte F, Dallapiccola B, Graham JM Jr, Saunders CJ, Bertini E, Kahn RA, Koolen DA, Tartaglia M. Biallelic Mutations in TBCD, Encoding the Tubulin Folding Cofactor D, Perturb Microtubule Dynamics and Cause Early-Onset Encephalopathy. Am J Hum Genet. 2016 Oct 6;99(4):962-973.

PubMed ID: 
27666370

Epileptic Encephalopathy, Early Infantile 48

Clinical Characteristics
Ocular Features: 

Poor eye contact is present from infancy.  Optic atrophy has been reported in several patients and features of retinitis pigmentosa were present in sibs of one family.

Systemic Features: 

Infants usually present with hypotonia and feeding difficulties.  Global developmental delay is also noted early and becomes more obvious with time.  Seizures are often seen early and become intractable.  Many individuals have microcephaly.  Hypermobility with dyskinesias and hyporeflexia are often present.  Speech is generally absent and many individuals are unable to sit or walk.

Brain imaging often shows atrophy of the cerebrum and cerebellum accompanied by enlarged ventricles and a thin corpus callosum.

Genetics

Homozygous or compound heterozygous mutations in the AP3B2 gene (15q25.2) can be responsible for this condition.

For another somewhat similar condition see early onset epileptic encephalopathy 28 (616211) with autosomal recessive inheritance.  For an autosomal dominant condition with a similar clinical picture, see early onset epileptic encephalopathy 47 (617166).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Autosomal-Recessive Mutations in AP3B2, Adaptor-Related Protein Complex 3 Beta 2 Subunit, Cause an Early-Onset Epileptic Encephalopathy with Optic Atrophy

Assoum M, Philippe C, Isidor B, Perrin L, Makrythanasis P, Sondheimer N, Paris C, Douglas J, Lesca G, Antonarakis S, Hamamy H, Jouan T, Duffourd Y, Auvin S, Saunier A, Begtrup A, Nowak C, Chatron N, Ville D, Mireskandari K, Milani P, Jonveaux P, Lemeur G, Milh M, Amamoto M, Kato M, Nakashima M, Miyake N, Matsumoto N, Masri A, Thauvin-Robinet C, Riviere JB, Faivre L, Thevenon J. Autosomal-Recessive Mutations in AP3B2, Adaptor-Related Protein Complex 3 Beta 2 Subunit, Cause an Early-Onset Epileptic Encephalopathy with Optic Atrophy. Am J Hum Genet. 2016 Dec 1;99(6):1368-1376.

PubMed ID: 
27889060

Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield

Anazi S, Maddirevula S, Faqeih E, Alsedairy H, Alzahrani F, Shamseldin HE, Patel N, Hashem M, Ibrahim N, Abdulwahab F, Ewida N, Alsaif HS, Al Sharif H, Alamoudi W, Kentab A, Bashiri FA, Alnaser M, AlWadei AH, Alfadhel M, Eyaid W, Hashem A, Al Asmari A, Saleh MM, AlSaman A, Alhasan KA, Alsughayir M, Al Shammari M, Mahmoud A, Al-Hassnan ZN, Al-Husain M, Osama Khalil R, Abd El Meguid N, Masri A, Ali R, Ben-Omran T, El Fishway P, Hashish A, Ercan Sencicek A, State M, Alazami AM, Salih MA, Altassan N, Arold ST, Abouelhoda M, Wakil SM, Monies D, Shaheen R, Alkuraya FS. Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield. Mol Psychiatry. 2016 Jul 19. doi: 10.1038/mp.2016.113. [Epub ahead of print].

PubMed ID: 
27431290

Encephalopathy, Early-Onset, With Brain Atrophy and Thin Corpus Callosum

Clinical Characteristics
Ocular Features: 

Optic atrophy is present in many patients and may be present early since lack of visual tracking or eye contact may be noted at birth.  Sparse eyebrows, upslanting palpebral fissures, and hypertelorism have also been reported.

Systemic Features: 

Severe hypotonia is present at birth often causing respiratory distress in the neonate.  Spasticity can develop later.  Growth failure with progressive microcephaly is present in infants.  Brain imaging often reveals diffuse atrophy of structures including the cerebellum, brainstem, spinal cord, and cerebrum.  Tongue fasciculations have been observed.   Micrognathia and widely spaced teeth are sometimes present.  Several patients have died during infancy.

Genetics

Homozygous mutations in the TBCD (17q25.3) are responsible for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Biallelic Mutations in TBCD, Encoding the Tubulin Folding Cofactor D, Perturb Microtubule Dynamics and Cause Early-Onset Encephalopathy

Flex E, Niceta M, Cecchetti S, Thiffault I, Au MG, Capuano A, Piermarini E, Ivanova AA, Francis JW, Chillemi G, Chandramouli B, Carpentieri G, Haaxma CA, Ciolfi A, Pizzi S, Douglas GV, Levine K, Sferra A, Dentici ML, Pfundt RR, Le Pichon JB, Farrow E, Baas F, Piemonte F, Dallapiccola B, Graham JM Jr, Saunders CJ, Bertini E, Kahn RA, Koolen DA, Tartaglia M. Biallelic Mutations in TBCD, Encoding the Tubulin Folding Cofactor D, Perturb Microtubule Dynamics and Cause Early-Onset Encephalopathy. Am J Hum Genet. 2016 Oct 6;99(4):962-973.

PubMed ID: 
27666370

Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy

Miyake N, Fukai R, Ohba C, Chihara T, Miura M, Shimizu H, Kakita A, Imagawa E, Shiina M, Ogata K, Okuno-Yuguchi J, Fueki N, Ogiso Y, Suzumura H, Watabe Y, Imataka G, Leong HY, Fattal-Valevski A, Kramer U, Miyatake S, Kato M, Okamoto N, Sato Y, Mitsuhashi S, Nishino I, Kaneko N, Nishiyama A, Tamura T, Mizuguchi T, Nakashima M, Tanaka F, Saitsu H, Matsumoto N. Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy. Am J Hum Genet. 2016 Oct 6;99(4):950-961.

PubMed ID: 
27666374

Retinitis Pigmentosa 77

Clinical Characteristics
Ocular Features: 

The onset of nyctalopia apparently varies from early childhood to 20 years of age and is usually the presenting symptom.  The loss of acuity is progressive (20/30 to 20/400) with older patients generally having more severe loss but there is little direct correlation with age.  Peripheral fields are progressively constricted, ranging from 10 to 30 degrees.  Some patients develop posterior subcapsular cataracts.  Retinal pigmentation is often mottled but 'bone spicules' are seen in about half of individuals.  Retinal vessels are narrowed.  The ERG shows generalized rod-cone dystrophy.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

Homozygous or compound heterozygous mutations in the REEP6 gene (19p13.3) are responsible for this disorder.  Five unrelated families have been reported.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported although cataract removal may be visually beneficial.  

References
Article Title: 

Mutations in REEP6 Cause Autosomal-Recessive Retinitis Pigmentosa

Arno G, Agrawal SA, Eblimit A, Bellingham J, Xu M, Wang F, Chakarova C, Parfitt DA, Lane A, Burgoyne T, Hull S, Carss KJ, Fiorentino A, Hayes MJ, Munro PM, Nicols R, Pontikos N, Holder GE; UKIRDC., Asomugha C, Raymond FL, Moore AT, Plagnol V, Michaelides M, Hardcastle AJ, Li Y, Cukras C, Webster AR, Cheetham ME, Chen R. Mutations in REEP6 Cause Autosomal-Recessive Retinitis Pigmentosa. Am J Hum Genet. 2016 Dec 1;99(6):1305-1315.

PubMed ID: 
27889258

Optic Atrophy 11

Clinical Characteristics
Ocular Features: 

Optic atrophy is seen as early as 5 years of age but may be congenital in origin as hypoplasia of the optic nerve was present in all patients.  Three of 4 affected children also were myopic.

Systemic Features: 

This is a form of mitochondriopathy with considerable clinical heterogeneity.  A single consanguineous family with 4 affected children of ages 5-16 years of age has been reported.

Common features include short stature, microcephaly (1 had macrocephaly), hearing impairment. Ataxia, dysmetria, and athetotic movements may be present.  Motor and mental development are delayed as is expressive speech.  Intellectual disability is present in all 4 patients.  Leukoencephalopathy was seen in all patients and one had brain atrophy.  Cerebellar hypoplasia was present in 2 of four patients.

Muscle mitochondria in one patient had morphologic changes.  Lactate levels and lactate/pyruvate ratios were elevated in the blood and CSF fluid of three patients.

Genetics

Homozygous mutations in the YME1L1 gene (10p12.1) were responsible for this condition in 4 offspring of a consanguineous Saudi Arabian family.   This is a nuclear encoded mitochondrial gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.Hom

References
Article Title: 

Anterior Segment Dysgenesis 6

Clinical Characteristics
Ocular Features: 

This is a congenital anterior segment dysplasia syndrome.  Iris hypoplasia with transillumination, corectopia, iridodenesis, and iridocorneal adhesions can be seen.  Increased intraocular pressure is a risk and ectopia lentis is often present.  Peters anomaly and defects in all layers of the cornea may be present.

No foveal hypoplasia is present.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

A single male patient of native American/French Canadian background has been reported with compound heterozygous mutations in the CYP1B1 gene (2p22.2).

See Anterior Chamber Dysgenesis 8 for another autosomal recessive disorder with somewhat similar clinical features.  Three families with 4 affected individuals have been reported with homozygous or compound heterozygous mutations in the CPAMD8 gene (19p13.11).

The genes FOXE3 and PAX6 are characterized as transcription factors and play important roles in ocular development.  However, while mutations in these are frequently found in patients with dysgenesis of the anterior chamber they often cause more widespread ocular and systemic anomalies (e.g., Gillespie syndrome [206700]).  Therefore in this database the anterior chamber constellations of anomalies associated with mutations in these genes are not considered to be simplex conditions.

See also related disorders iridogoniodysgenesis type 1 (601631) and type 2 (137600), and anterior segment mesenchymal dysgenesis (107250).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Lifelong pressure monitoring is important.

References
Article Title: 

Phenotypic heterogeneity of CYP1B1: mutations in a patient with Peters' anomaly

Vincent A, Billingsley G, Priston M, Williams-Lyn D, Sutherland J, Glaser T, Oliver E, Walter MA, Heathcote G, Levin A, Heon E. Phenotypic heterogeneity of CYP1B1: mutations in a patient with Peters' anomaly. J Med Genet. 2001 May;38(5):324-6. PubMed PMID: 11403040; PubMed Central PMCID: PMC1734880.

PubMed ID: 
11403040

Anterior Segment Dysgenesis 8

Clinical Characteristics
Ocular Features: 

This is a congenital anterior segment dysplasia syndrome with considerable clinical heterogeneity.  Iris hypoplasia with transillumination, corectopia, iridodenesis, and iridocorneal adhesions are often seen.  Intraocular pressure may be elevated in older individuals.  Ectopia lentis is often present.  Lenticular opacities consisting primarily of posterior cortical opacification are common.  Visual acuity varies from 6/6 to 6/24.

No foveal hypoplasia is present but one of four reported patients was described with bilateral optic nerve dysplasia.     

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

Three families with 4 affected individuals with similar clinical features have been reported with homozygous or compound heterozygous mutations in the CPAMD8 gene (19p13.11).

A single male patient of native American/French Canadian background with somewhat similar clinical features has been reported with compound heterozygous mutations in the CYP1B1 gene (2p22.2) but this is likely a unique condition (Anterior Segment Dysgenesis 6).

The genes FOXE3 and PAX6 are characterized as transcription factors and play important roles in ocular development.  However, while mutations in these are frequently found in patients with dysgenesis of the anterior chamber they often cause more widespread ocular and systemic anomalies (e.g., Gillespie syndrome [206700]).  Therefore in this database the anterior chamber constellations of anomalies associated with mutations in these genes are not considered to be simplex conditions. 

See also related disorders iridogoniodysgenesis type 1 (601631) and type 2 (137600), and anterior segment mesenchymal dysgenesis (107250).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Several patients have had cataract surgery.  Monitoring intraocular pressure throughout life is necessary and prompt treatment for glaucoma is important.

References
Article Title: 

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