hypotonia

Spastic Paraplegia 75

Clinical Characteristics
Ocular Features: 

Nystagmus with optic atrophy is usually present and one individual had glaucoma. 

Systemic Features: 

This is an early-onset and progressive neurodegenerative disorder.  Hypotonia may be present at birth.  A spastic gait and difficulty walking is noted in early childhood and most individuals never walk unassisted. Yong adults have spastic paresis with extensor plantar responses and clonus has been reported.  Distal muscle atrophy in the lower extremities has been noted.  Speech is dysarthric.  Brain imaging has been normal in some patients whereas others have mild atrophy of the cerebellum and the corpus callosum.  Cognitive impairment is variable with some individuals showing poor school performance while others are described as mentally retarded.

Genetics

Homozygous mutations in the MAG gene (19q13.12) are responsible for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported although physical therapy may be helpful. Special education, speech and physical therapy, and low vision devices might also be of benefit.

References
Article Title: 

Myelin-associated glycoprotein gene mutation causes Pelizaeus-Merzbacher disease-like disorder

Lossos A, Elazar N, Lerer I, Schueler-Furman O, Fellig Y, Glick B, Zimmerman BE, Azulay H, Dotan S, Goldberg S, Gomori JM, Ponger P, Newman JP, Marreed H, Steck AJ, Schaeren-Wiemers N, Mor N, Harel M, Geiger T, Eshed-Eisenbach Y, Meiner V, Peles E. Myelin-associated glycoprotein gene mutation causes Pelizaeus-Merzbacher disease-like disorder. Brain. 2015 Sep;138(Pt 9):2521-36.

PubMed ID: 
26179919

Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders

Novarino G, Fenstermaker AG, Zaki MS, Hofree M, Silhavy JL, Heiberg AD, Abdellateef M, Rosti B, Scott E, Mansour L, Masri A, Kayserili H, Al-Aama JY, Abdel-Salam GM, Karminejad A, Kara M, Kara B, Bozorgmehri B, Ben-Omran T, Mojahedi F, Mahmoud IG, Bouslam N, Bouhouche A, Benomar A, Hanein S, Raymond L,Forlani S, Mascaro M, Selim L, Shehata N, Al-Allawi N, Bindu PS, Azam M, Gunel M, Caglayan A, Bilguvar K, Tolun A, Issa MY, Schroth J, Spencer EG, Rosti RO, Akizu N, Vaux KK, Johansen A, Koh AA, Megahed H, Durr A, Brice A, Stevanin G, Gabriel SB, Ideker T, Gleeson JG. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science. 2014 Jan 31;343(6170):506-11.

PubMed ID: 
24482476

Cleft Palate, Psychomotor Retardation, and Distinctive Facial Features

Clinical Characteristics
Ocular Features: 

The facial dysmorphism is present at birth together with the cleft palate.  Downslanting lid fissures, widely spaced eyes, and ptosis may be present.  Eyebrows have been described as sparse in one patient.  Strabismus and ocular apraxia are present in some children. 

Systemic Features: 

Three patients have been reported, one of whom also had a second deletion in a gene implicated in the Kabuki syndrome.  This individual had hypertrichosis and synophyrys whereas the others had sparse eyebrow and temporal hair.  The teeth are malformed with some conically shaped and widely spaced.  The forehead is prominent and the fingers are tapered and brachydactylous with 5th finger clinodactyly.

There are significant delays in achieving developmental milestones.  Hypotonia has been described.  Speech and walking in particular may be delayed for several years.   Physical growth may be delayed as well.  A variety of brain anomalies have been seen in some but not all individuals.  Hypospadius and cryptorchidism have been described.  All children reported have palatal anomalies.

Genetics

Heterozygous mutations in the KDM1A gene have been identified in two patients.  In another report a single patient had an out-of-frame 3-nucleotide deletion in the ANKRD11 gene (as sometimes found in Kabuki syndrome) plus a mutation in the KDM1A gene. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features

Chong JX, Yu JH, Lorentzen P, Park KM, Jamal SM, Tabor HK, Rauch A, Saenz MS, Boltshauser E, Patterson KE, Nickerson DA, Bamshad MJ. Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features. Genet Med. 2015 Dec 10. doi: 10.1038/gim.2015.161. [Epub ahead of print].

PubMed ID: 
26656649

Vici Syndrome

Clinical Characteristics
Ocular Features: 

Congenital cataracts, both unilateral and bilateral are common.  The fundus appears hypopigmented. Nystagmus, optic neuropathy, and mild ptosis have been reported.  Nothing is known regarding acuity. 

Systemic Features: 

Infants at birth have striking hypotonia with a weak cry and feeding difficulties.  Dysmorphic features such as micrognathia, microcephaly, low-set ears, some degree of generalized hypopigmentation (hair and skin), and a broad nose with a long philtrum may be present. The face may appear triangular.  Cleft lip and palate may be present.  Evidence of cardiac dysfunction may also be present early with both dilated and hypertrophic cardiomyopathy reported.  Hearing loss has been reported in some individuals.  Recurrent infections are common and immunologic studies have revealed, in some patients, granulocytopenia, low T cell counts (primarily T4+ cells), thymic dysplasia, and low levels of IgG.  Seizures may occur.  Liver dysfunction has been variably reported.

Neurological and brain evaluations have reported agenesis of the corpus callosum, defects in the septum pellucidum, and hypoplasia of the cerebellar vermis along with pontocerebellar hypoplasia.  Psychomotor retardation is severe in most individuals along with general growth retardation.

Histologic studies of skeletal muscle fibers have shown considerable variation in fiber size, centralized nuclei, fucsinophilic inclusions, and enlarged abnormal mitochondria.  Other central nervous system abnormalities include in some individuals a paucity of white matter, schizencephaly, neuronal heterotopias, and enlargement of the ventricles.

The cumulative effects of these multiorgan abnormalities lead to death within the first year or two of life, generally of heart failure or sepsis. 

Genetics

Homozygous or compound heterozygous mutations in the EPG5 gene (18q12.3) have been associated with this condition.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Vici syndrome: a

Byrne S, Dionisi-Vici C, Smith L, Gautel M, Jungbluth H. Vici syndrome: a
review. Orphanet J Rare Dis. 2016 Feb 29;11(1):

PubMed ID: 
4772338

Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy

Cullup T, Kho AL, Dionisi-Vici C, Brandmeier B, Smith F, Urry Z, Simpson MA, Yau S, Bertini E, McClelland V, Al-Owain M, Koelker S, Koerner C, Hoffmann GF, Wijburg FA, ten Hoedt AE, Rogers RC, Manchester D, Miyata R, Hayashi M, Said E, Soler D, Kroisel PM, Windpassinger C, Filloux FM, Al-Kaabi S, Hertecant J, Del Campo M, Buk S, Bodi I, Goebel HH, Sewry CA, Abbs S, Mohammed S, Josifova D, Gautel M, Jungbluth H. Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. Nat Genet. 2013 Jan;45(1):83-7.

PubMed ID: 
23222957

Infantile Cerebellar-Retinal Degeneration

Clinical Characteristics
Ocular Features: 

Visual tracking can be normal during the newborn period but lack of visual fixation and attention soon become evident.  Strabismus, nystagmus, and abnormal pursuit movements are often present.  Optic atrophy has been reported as early as 3 years of age.  VEP and ERG responses are extinguished in the first two years. The nystagmus may be multidirectional.  Acuity loss seems to be progressive.  A progressive retinal degeneration (not further characterized) has been reported.

Systemic Features: 

Infants generally appear normal at birth.  Within the first 6 months they show signs of developmental delay and neurological signs such as truncal hypotonia, seizures, athetosis and head bobbing.  Milestones of sitting, rolling over, and reactions to others are seldom achieved.  Cerebellar brain imaging shows progressive atrophy in all patients and some have cortical atrophy as well.  Some patients have evidence of hearing loss.   Severe failure to thrive and psychomotor delays are usually present.  Death may occur within several months of birth although some live for several decades.

Genetics

This condition results from homozygous or compound heterozygous mutations in the ACO2 gene (22q13.2).  The mutation has also been associated with optic atrophy 9 (616289).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment beyond supportive care is known.

References
Article Title: 

Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy

Metodiev MD, Gerber S, Hubert L, Delahodde A, Chretien D, Gerard X, Amati-Bonneau P, Giacomotto MC, Boddaert N, Kaminska A, Desguerre I, Amiel J, Rio M, Kaplan J, Munnich A, Rotig A, Rozet JM, Besmond C. Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy. J Med Genet. 2014 Dec;51(12):834-8.

PubMed ID: 
25351951

PEHO Syndrome

Clinical Characteristics
Ocular Features: 

Optic atrophy is a common feature.  There may be lack of visual fixation from birth or sometimes several months later, attributed to cortical inattention.  Flash visual evoked potentials may be unrecordable. Pupillary responses to light are 'weak' and sluggish. Epicanthal folds may be seen.

Systemic Features: 

Infants are usually born with a normal head circumference but fall behind (2 SD or more) in the first year.  They have neonatal and infantile central hypotonia with brisk peripheral tendon reflexes during early childhood.  They are sometimes described as drowsy or lethargic.  Facial and limb edema can be extensive but transient sometimes and can disappear later in childhood.  The fingers are tapered.  The cheeks are full, the mouth is usually open and the upper lip appears 'tented'.  Global developmental delay is common and normal milestones are seldom attained.  Some patients have been described as severely retarded mentally.  Infantile spasms and myoclonic jerkingcan be seen within the first months of life while frank seizures with hypsarrhythmia are common in the first year of life.  Status epilepticus is a common occurrence.  General drowsiness and poor feeding are often features.  Death usually occurs in infancy or early childhood.  Midface hypoplasia and micrognathia are often present.

Brain imaging (MRI) and histology show severe alterations in myelination and cellular organization.  Neuronal loss is seen in the inner granular layer of the cerebellum but there is relative preservation of Purkinje cells.  General and progressive atrophy of the cerebellum and brain stem have been described.

Genetics

Homozygous frameshift mutations in ZNHIT3 (17q12) have been identified in affected members of several consanguineous families.  The presumed mutation seems to be most prevalent in Finland.

A somewhat similar disorder known as PEHO-like syndrome (617507) is the result of homozygous mutations in the CCDC88A gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Physical therapy to prevent contractures and general supportive care can be helpful.  Supplemental feeding may be required. 

References
Article Title: 

The PEHO syndrome

Riikonen R. The PEHO syndrome. Brain Dev. 2001 Nov;23(7):765-9. Review.

PubMed ID: 
11701291

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

Mental Retardation, AD 34

Clinical Characteristics
Ocular Features: 

Patients may have upslanting lid fissures, epicanthus, ptosis, synophrys, and cortical visual impairment.

Systemic Features: 

Among the three reported individuals with the COL4A3BP mutation, one had postnatal microcephaly, widely spaced teeth, synophrys, and intellectual disability. Another had trunk hypotonia, global developmental delay, wide intermamillary distance, 2-3 toe syndactyly, tonic-clonic seizures, and myopathic facies. The third had a broad-based gait, coarse and curly hair, tonic-clonic seizures, and global developmental delay. 

Genetics

In a screening study of 1133 children with severe undiagnosed developmental conditions, three males were found with heterozygous mutations in the COL4A3BP gene (5q13).  Family history data are not given for these three individuals but autosomal dominant transmission seems to be a reasonable assumption.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Supportive care is required but no other treatment has been reported.

References
Article Title: 

Singleton-Merten Syndrome 1

Clinical Characteristics
Ocular Features: 

Several children have been diagnosed with glaucoma in early childhood or during puberty.  Glaucoma surgery has been beneficial in some but visual damage may be severe.

Systemic Features: 

Patients have early-onset calcifications of the aorta and of the aortic and mitral valves which may be seen in childhood and can be responsible for heart failure and early death.  Osteoporosis of the limbs and widened medullary cavities have been seen.  Abnormal bone mineralization and extends to the jaws leading to tooth loss and early-onset periodontal disease.  Eruption of both primary and permanent teeth is delayed but tooth roots can be truncated as well.  The hips dislocate easily due to shallow acetabulae and patients are susceptible to tendon tears.

Hypotonia and generalized weakness may be present which is sometimes exacerbated following a febrile illness.  The skin may be dry and scaly consistent with psoriasis and there may be photosensitivity.

The forehead is broad and prominent and the hairline is high and anterior.  The philtrum is smooth and the upper vermilion is thin.

Genetics

Heterozygous mutations in the IFIH1 gene (2q24.2) are responsible for this disorder.  Another form of Singleton-Merten Syndrome (SGMRT2; 609631) is the result of mutations in the DDX58 gene. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is directed at specific problems such as fractures, glaucoma, and periodontal disease.

References
Article Title: 

A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome

Rutsch F, MacDougall M, Lu C, Buers I, Mamaeva O, Nitschke Y, Rice GI, Erlandsen H, Kehl HG, Thiele H, Nurnberg P, Hohne W, Crow YJ, Feigenbaum A, Hennekam RC. A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome. Am J Hum Genet. 2015 Feb 5;96(2):275-82.

PubMed ID: 
25620204

Kaufman Oculocerebrofacial Syndrome

Clinical Characteristics
Ocular Features: 

Alterations in the morphology of periocular structures is the most consistent ocular feature.  These include epicanthal folds, upward-slanting lid fissures, ptosis, blepharophimosis, sparse eyebrows, and telecanthus.  However, pale optic discs, iris colobomas, microcornea, strabismus, nystagmus, and hypertelorism are variably present. 

Systemic Features: 

There is both intrauterine and postnatal growth retardation.  Hypotonia is often noted along with general psychomotor delays.  Neonatal respiratory distress and laryngeal stridor may be present.  The intellectual disability can be severe.  Corpus callosum aplasia and hypoplasia have been reported.  Microcephaly and brachycephaly with delayed suture closure are features.  The face is long and narrow and the mouth is disproportionally large.  A high arched palate can be present and the pinnae are often deformed, posteriorly rotated and may be accompanied by preauricular skin tags. The teeth appear widely spaced (diastema) and the lower jaw is underdeveloped.

Genetics

Kaufman BPIDS syndrome results from homozygous or compound heterozygous mutations in the UBE3B gene (12q23).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No general treatment is available although repair of some specific malformations is possible.

References
Article Title: 

Deficiency for the ubiquitin ligase UBE3B in a blepharophimosis-ptosis-intellectual-disability syndrome

Basel-Vanagaite L, Dallapiccola B, Ramirez-Solis R, Segref A, Thiele H, Edwards A, Arends MJ, Miro X, White JK, Desir J, Abramowicz M, Dentici ML, Lepri F, Hofmann K, Har-Zahav A, Ryder E, Karp NA, Estabel J, Gerdin AK, Podrini C, Ingham NJ, Altmuller J, Nurnberg G, Frommolt P, Abdelhak S, Pasmanik-Chor M, Konen O, Kelley RI, Shohat M, Nurnberg P, Flint J, Steel KP, Hoppe T, Kubisch C, Adams DJ, Borck G. Deficiency for the ubiquitin ligase UBE3B in a blepharophimosis-ptosis-intellectual-disability syndrome. Am J Hum Genet. 2012 Dec 7;91(6):998-1010.

PubMed ID: 
23200864

An oculocerebrofacial syndrome

Kaufman RL, Rimoin DL, Prensky AL, Sly WS. An oculocerebrofacial syndrome. Birth Defects Orig Artic Ser. 1971 Feb;7(1):135-8.

PubMed ID: 
5006210

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