feeding difficulties

Leukodystrophy, Hypomyelinating, 13

Clinical Characteristics
Ocular Features: 

Several individuals in one family have been observed with optic atrophy, nystagmus and visual impairment.

Systemic Features: 

Head circumference is normal at birth but later in childhood falls behind in growth.  Neurodevelopment seems to plateau without regression.  Feeding difficulties may be present from birth and may require gastroscopy tube placement.  Motor skills are delayed and expressive language may never develop.  General irritability and increased muscle tone with hyperreflexia are usually present eventually resulting in joint contractures. 

EEGs , electromyography, and nerve conduction studies have been normal in 3 patients.  A brain MRI in one patient showed a leukodystrophic pattern in periventricular areas.  Variable cardiac malfunctions such as heart failure, LVH, and pericarditis were observed in several patients.

Sudden death following a short febrile illness has been reported to occur in three of the six affected children before the age of 15 years. 

Genetics

Homozygous mutations in the C11ORF73 gene (11q14.2) are responsible for this disorder.  Three unrelated families of Ashkenazi Jewish descent have been reported.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported.

References
Article Title: 

Hypotonia, Infantile, with Psychomotor Retardation

Clinical Characteristics
Ocular Features: 

Abducens nerve palsy with characteristic strabismus (esotropia) can be present.

Systemic Features: 

Mothers may note decreased fetal movements.  Severe generalized hypotonia can be evident at birth, requiring tube feeding and respiratory assistance.  Death may occur before 6 months of age but with intense supportive care children can live for several years.  Brain imaging may show enlarged lateral ventricles and thinning of the corpus callosum in some individuals but no abnormalities in others.  Muscle biopsies can show severe myopathic changes with increased fibrosis, variation in fiber size, and small atrophic fibers.  Cardiac septal defects have been reported.  Delayed psychomotor development is a common feature.

Genetics

Homozygous mutations in the CCDC174 gene (3p25.1) are responsible for this condition so far reported in only two families with 6 children affected.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known for this condition.

References
Article Title: 

CDC174, a novel

Volodarsky M, Lichtig H, Leibson T, Sadaka Y, Kadir R, Perez Y, Liani-Leibson
K, Gradstein L, Shaco-Levy R, Shorer Z, Frank D, Birk OS. CDC174, a novel
component of the exon junction complex whose mutation underlies a syndrome of
hypotonia and psychomotor developmental delay. Hum Mol Genet. 2015 Nov
15;24(22):6485-91.

PubMed ID: 
26358778

3-methylglutaconic Aciduria with Cataracts, Neurologic Involvement and Neurtropenia

Clinical Characteristics
Ocular Features: 

Descriptions of ocular findings have been limited.  Congenital nuclear cataracts have been described in one patient but lens opacities have been noted in others.

Systemic Features: 

There is considerable heterogeneity in the phenotype with some patients having minimal signs and living to adulthood whereas others succumb to their disease in the first year of life.  The onset of progressive encephalopathy usually occurs in infancy as evidenced by various movement abnormalities and psychomotor delays.  Neonatal hypotonia sometimes progresses to spasticity.  However, other infants are neurologically normal.  Delayed psychomotor development, ataxia, seizures, and dystonia may be seen.  Brain imaging may reveal cerebellar and cerebral atrophy along with brain stem abnormalities.  Neuronal loss, diffuse gliosis, and microvacuolization have been seen on neuropathologic examination.  Dysphagia is common.  Severe neutropenia and recurrent infections may begin in infancy as well.

Increased amounts of 3-methylglutaconic acid are found in the urine while the bone marrow may contain evidence of arrested granulopoiesis. 

Genetics

This autosomal recessive disorder results from homozygous or compound heterozygous mutations in the CLPB gene (11q13.4).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported for this condition.

References
Article Title: 

CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder

Wortmann SB, Zietkiewicz S, Kousi M, Szklarczyk R, Haack TB, Gersting SW, Muntau AC, Rakovic A, Renkema GH, Rodenburg RJ, Strom TM, Meitinger T, Rubio-Gozalbo ME, Chrusciel E, Distelmaier F, Golzio C, Jansen JH, van Karnebeek C, Lillquist Y, Lucke T, Ounap K, Zordania R, Yaplito-Lee J, van Bokhoven H, Spelbrink JN, Vaz FM, Pras-Raves M, Ploski R, Pronicka E, Klein C, Willemsen MA, de Brouwer AP, Prokisch H, Katsanis N, Wevers RA. CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder. Am J Hum Genet. 2015 Feb 5;96(2):245-57.

PubMed ID: 
25597510

Nemaline Myopathy 10

Clinical Characteristics
Ocular Features: 

Ophthalmoplegia has been reported in 29% of patients.

Systemic Features: 

In this form of nemaline myopathy, polyhydramnios, weak or absent fetal movements, and joint contractures may be noted during the antenatal period.  Hypotonia and generalized weakness, respiratory difficulties, feeding difficulties and evidence of bulbar weakness may be noted at birth.  Many patients die of respiratory failure in the neonatal period but some may survive into the second decade. 

Cardiac function is normal.

Genetics

This autosomal recessive disorder results from homozygous or compound heterozygous mutations in the LMOD3 gene (3p14.1).  This gene is expressed in both skeletal and cardiac muscle and its product is essential for the organization of sarcomeric thin filaments in skeletal muscle.

Mutations in at least 10 genes cause nemaline myopathy.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No general treatment is available for this condition but supportive care such as respiratory assistance and feeding supplementation may be helpful.  Physical therapy and special education may be helpful.

References
Article Title: 

Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy

Yuen M, Sandaradura SA, Dowling JJ, Kostyukova AS, Moroz N, Quinlan KG, Lehtokari VL, Ravenscroft G, Todd EJ, Ceyhan-Birsoy O, Gokhin DS, Maluenda J, Lek M, Nolent F, Pappas CT, Novak SM, D'Amico A, Malfatti E, Thomas BP, Gabriel SB, Gupta N, Daly MJ, Ilkovski B, Houweling PJ, Davidson AE, Swanson LC, Brownstein CA, Gupta VA, Medne L, Shannon P, Martin N, Bick DP, Flisberg A, Holmberg E, Van den Bergh P, Lapunzina P, Waddell LB, Sloboda DD, Bertini E, Chitayat D, Telfer WR, Laquerriere A, Gregorio CC, Ottenheijm CA, Bonnemann CG, Pelin K, Beggs AH, Hayashi YK, Romero NB, Laing NG, Nishino I, Wallgren-Pettersson C, Melki J, Fowler VM, MacArthur DG, North KN, Clarke NF. Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy. J Clin Invest. 2014 Nov;124(11):4693-708. Erratum in: J Clin Invest. 2015 Jan;125(1):456-7.

PubMed ID: 
25250574

Kabuki Syndrome 2

Clinical Characteristics
Ocular Features: 

The facial features are characteristic primarily because of the appearance of the periocular features.  The eyebrows are highly arched and sparse.  The lid fissures are long with eversion of the lateral portion of the lower eyelid.  The eyelashes are bushy.  Nystagmus and strabismus have been reported.

Systemic Features: 

Only a small number of individuals with Kabuki syndrome 2 have been reported and the phenotype is incompletely described.  Most of the features in type 2 are similar to those in type 1 with defects in multiple organs.  There are often cardiac malformations including septal defects.  Otitis media and hearing loss are common.  The pinnae are large and cupped.  A highly arched or cleft palate may be present and the teeth are usually small.  The joints are highly mobile and general hypotonia is often present. The fifth finger is often short and clinodactylous.  Persistent fetal fingerpads are common.  The amount of intellectual disability varies considerably with some patients functioning normally.  Urogenital anomalies are less common than found in Kabuki syndrome 1 and anal malformations do not seem to be a feature.

Genetics

Kabuki syndrome 2 is an X-linked disorder, usually as the result of a mutation in the KDM6A gene (Xp11.3).   Patients with the X-linked form of Kabuki represent about 5-10% of cases.   

Kabuki syndrome 1 (147920) is an autosomal dominant condition caused by heterozygous mutations in the KMT2D gene but remaining heterogeneity is suggested by the fact that a substantial proportion (30%) of individuals with Kabuki syndrome features has neither of these mutations.

In a 3 generation family two males had the typical Kabuki phenotype whereas their mother and grandmother (all had the KMT2D mutation) had various attenuated features.

Treatment
Treatment Options: 

Management guidelines are available (Management of Kabuki Syndrome).

References
Article Title: 

Molecular analysis, pathogenic mechanisms, and readthrough therapy on a large cohort of Kabuki syndrome patients

Micale L, Augello B, Maffeo C, Selicorni A, Zucchetti F, Fusco C, De Nittis P, Pellico MT, Mandriani B, Fischetto R, Boccone L, Silengo M, Biamino E, Perria C, Sotgiu S, Serra G, Lapi E, Neri M, Ferlini A, Cavaliere ML, Chiurazzi P, Monica MD, Scarano G, Faravelli F, Ferrari P, Mazzanti L, Pilotta A, Patricelli MG, Bedeschi MF, Benedicenti F, Prontera P, Toschi B, Salviati L, Melis D, Di Battista E, Vancini A, Garavelli L, Zelante L, Merla G. Molecular analysis, pathogenic mechanisms, and readthrough therapy on a large cohort of Kabuki syndrome patients. Hum Mutat. 2014 Jul;35(7):841-50.

PubMed ID: 
24633898

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