respiratory insufficiency

Mental Retardation, AD 31

Clinical Characteristics
Ocular Features: 

A variety of ocular dysmorphisms have been described in this disorder including up-slanting lid fissures, epicanthal folds, hypertelorism, and telecanthus.  Ptosis was described in 1 patient.  Strabismus, nystagmus, and disconjugate gaze have been observed.  Visual acuity has not been reported but "variable visual impairment" has been described.  One patient was considered to have cortical visual impairment.

Systemic Features: 

Neonatal hypotonia and feeding difficulties are among the first signs along with seizure-like activity (50%) including infantile spasms.  EEG anomalies are present in the majority of individuals.  Gastroscopy tubes may be required in a significant minority of patients.  Hypotonic or myopathic facies is common.  Apneic episodes may be seen in the neonatal period and most infants have respiratory difficulties in the first year of life which may improve during this period.  Learning difficulties and features of autism are common.  Some patients are unable to walk while others have an ataxic or broad-based gait.  Speech may be absent or severely limited.  The forehead is prominent while the hard palate is usually highly vaulted.

Brain MRIs may show delayed myelination but such scans have been described as normal in other individuals.  Enlarged ventricles, a thin corpus callosum, and periventricular white matter changes may also be present.   Neuropathologic studies have revealed chronic inflammatory changes around the arterioles of deep while matter.

Genetics

Heterozygous mutations in the PURA gene (5q31) have been identified in this disorder.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Expanding the neurodevelopmental phenotype of PURA syndrome

Lee BH, Reijnders MRF, Abubakare O, Tuttle E, Lape B, Minks KQ, Stodgell C, Bennetto L, Kwon J, Fong CT, Gripp KW, Marsh ED, Smith WE, Huq AM, Coury SA, Tan WH, Solis O, Mehta RI, Leventer RJ, Baralle D, Hunt D, Paciorkowski AR. Expanding the neurodevelopmental phenotype of PURA syndrome. Am J Med Genet A. 2018 Jan;176(1):56-67.

PubMed ID: 
29150892

De novo mutations in PURA are associated with hypotonia and developmental delay

Tanaka AJ, Bai R, Cho MT, Anyane-Yeboa K, Ahimaz P, Wilson AL, Kendall F, Hay B, Moss T, Nardini M, Bauer M, Retterer K, Juusola J, Chung WK. De novo mutations in PURA are associated with hypotonia and developmental delay. Cold Spring Harb Mol Case Stud. 2015 Oct;1(1):a000356. doi: 10.1101/mcs.a000356.

PubMed ID: 
27148565

Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome

Lalani SR, Zhang J, Schaaf CP, Brown CW, Magoulas P, Tsai AC, El-Gharbawy A, Wierenga KJ, Bartholomew D, Fong CT, Barbaro-Dieber T, Kukolich MK, Burrage LC, Austin E, Keller K, Pastore M, Fernandez F, Lotze T, Wilfong A, Purcarin G, Zhu W, Craigen WJ, McGuire M, Jain M, Cooney E, Azamian M, Bainbridge MN, Muzny DM, Boerwinkle E, Person RE, Niu Z, Eng CM, Lupski JR, Gibbs RA, Beaudet AL, Yang Y, Wang MC, Xia F. Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome. Am J Hum Genet. 2014 Nov 6;95(5):579-83.

PubMed ID: 
25439098

Brown-Vialetto-Van Laere Syndrome 2

Clinical Characteristics
Ocular Features: 

Decreased vision, optic atrophy, and nystagmus are frequently present.  Pupillary reflexes may be absent.

Systemic Features: 

Rapidly progressive muscle weakness and ataxia present in childhood.  Early development may be normal but the first symptoms usually appear by age 2 or 3 years of age.  Cognition is usually normal.  Exercise intolerance soon appears along with dysphonia, dyspnea, dysphagia, and weakness of shoulder, neck and axial muscles.  Wasting and weakness of hand muscles is often noticeable.  Kyphoscoliosis, tongue fasciculations, and areflexia are often seen.  Sensorineural hearing loss is a common feature.

Death from respiratory insufficiency often occurs within a few years after onset.

Genetics

Homozygous mutations in the SLC52A2 (8q24.3) gene have been identified in patients with this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Administration of riboflavin has been reported to be beneficial in lessening symptoms.

References
Article Title: 

SLC52A2 mutations cause SCABD2 phenotype: A second report

Babanejad M, Adeli OA, Nikzat N, Beheshtian M, Azarafra H, Sadeghnia F, Mohseni M, Najmabadi H, Kahrizi K. SLC52A2 mutations cause SCABD2 phenotype: A second report. Int J Pediatr Otorhinolaryngol. 2018 Jan;104:195-199.

PubMed ID: 
29287867

Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2

Foley AR, Menezes MP, Pandraud A, Gonzalez MA, Al-Odaib A, Abrams AJ, Sugano K, Yonezawa A, Manzur AY, Burns J, Hughes I, McCullagh BG, Jungbluth H, Lim MJ, Lin JP, Megarbane A, Urtizberea JA, Shah AH, Antony J, Webster R, Broomfield A, Ng J, Mathew AA, O'Byrne JJ, Forman E, Scoto M, Prasad M, O'Brien K, Olpin S, Oppenheim M, Hargreaves I, Land JM, Wang MX, Carpenter K, Horvath R, Straub V, Lek M, Gold W, Farrell MO, Brandner S, Phadke R, Matsubara K, McGarvey ML, Scherer SS, Baxter PS, King MD, Clayton P, Rahman S, Reilly MM, Ouvrier RA, Christodoulou J, Zuchner S, Muntoni F, Houlden H. Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2. Brain. 2014 Jan;137(Pt 1):44-56.

PubMed ID: 
24253200

Carey-Fineman-Ziter Syndrome

Clinical Characteristics
Ocular Features: 

Abnormal eye movements with prominent external ophthalmoplegia are hallmarks of this disease.  An oculomotor nerve palsy with limited abduction and some degree of facial palsy are usually present.  The Moebius sequence is present in many patients.  Epicanthal folds, downslanting lid fissures, and ptosis are frequently seen.

Systemic Features: 

Clinical signs are highly variable.  Unusual facies with features of the Pierre Robin complex are characteristic.  Micrognathia and retrognathia are often present with glossoptosis.  Hypotonia and failure to thrive are commonly seen.  Dysphagia and even absent swallowing likely contribute to this.  Respiratory insufficiency can be present from birth, often with laryngostenosis, and some patients develop pulmonary hypertension and restrictive lung disease as adults.  Progressive scoliosis may contribute to this.  Many patients have club feet with joint contractures.  Skull formation consisting of microcephaly, or macrocephaly, or plagiocephaly is commonly seen.  Cardiac septal defects are common.

Intellectual disability is present in some but not all individuals.  Neuronal heterotopias, enlarged ventricles, reduced white matter, a small brainstem, microcalcifications, and enlarged ventricles have been observed.

Genetics

Homozygous or compound heterozygosity of the MYMK gene (9q34) is responsible for this condition.  

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment for the general disorder has been reported.

References
Article Title: 

A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome

Di Gioia SA, Connors S, Matsunami N, Cannavino J, Rose MF, Gilette NM, Artoni P, de Macena Sobreira NL, Chan WM, Webb BD, Robson CD, Cheng L, Van Ryzin C, Ramirez-Martinez A, Mohassel P, Leppert M, Scholand MB, Grunseich C, Ferreira CR, Hartman T, Hayes IM, Morgan T, Markie DM, Fagiolini M, Swift A, Chines PS, Speck-Martins CE, Collins FS, Jabs EW, Bonnemann CG, Olson EN; Moebius Syndrome Research Consortium, Carey JC, Robertson SP, Manoli I, Engle EC. A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome. Nat Commun. 2017 Jul 6;8:16077. doi: 10.1038/ncomms16077.

PubMed ID: 
28681861

Möbius sequence, Robin complex, and hypotonia: severe expression of brainstem disruption spectrum versus Carey-Fineman-Ziter syndrome

Verloes A, Bitoun P, Heuskin A, Amrom D, van de Broeck H, Nikkel SM, Chudley AE, Prasad AN, Rusu C, Covic M, Toutain A, Moraine C, Parisi MA, Patton M, Martin JJ, Van Thienen MN. Mobius sequence, Robin complex, and hypotonia: severe expression of brainstem disruption spectrum versus Carey-Fineman-Ziter syndrome. Am J Med Genet A. 2004 Jun 15;127A(3):277-87.

PubMed ID: 
15150779

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

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

Osteogenesis Imperfecta, Type VII

Clinical Characteristics
Ocular Features: 

Shallow orbits sometimes lead to severe and even progressive proptosis.  Bluish sclerae are sometimes present.

Systemic Features: 

Infants may be born with multiple fractures and adults are often short in stature.  Hypoplasia of the midface, frontal bossing, sutural craniosynostosis, hydrocephalus, and shallow orbits are frequently present and contribute to what is sometimes considered a distinctive facial dysmorphism.  Dentinogenesis imperfecta and hearing loss are variable features.  Neurological development is normal.

Multiple fractures occur and may result in marked long bone deformities, scoliosis, and short stature.  When the ribs are involved, respiratory insufficiency may result and can be responsible for early death.  Type VII osteogenesis imperfecta is sometimes considered a lethal form of OI. 

Genetics

Homozygous mutations in the CRTAP gene (3p22.3) are responsible for this condition.  This gene codes for a cartilage-associated protein and in mice is highly expressed in chondrocytes at growth plates and around the chondroosseous junction.  

This condition has been confused with Cole-Carpenter 1 syndrome (112240) but the latter is due to heterozygous mutations in P4HB (17q25.3) (PDI gene family).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Fractures require stabilization and hydrocephalus, if present, needs to be treated promptly.  Extreme proptosis can lead to inadequate hydration of the eye (especially the cornea) that may require lid surgery or orbital reconstruction.

References
Article Title: 

CRTAP mutation in a patient with Cole-Carpenter syndrome

Balasubramanian M, Pollitt RC, Chandler KE, Mughal MZ, Parker MJ, Dalton A, Arundel P, Offiah AC, Bishop NJ. CRTAP mutation in a patient with Cole-Carpenter syndrome. Am J Med Genet A. 2015 Jan 21. doi: 10.1002/ajmg.a.36916. [Epub ahead of print].

PubMed ID: 
25604815

New case of Cole-Carpenter syndrome

Amor DJ, Savarirayan R, Schneider AS, Bankier A. New case of Cole-Carpenter syndrome. Am J Med Genet. 2000 Jun 5;92(4):273-7. Review.

PubMed ID: 
10842295

Myotonic Dystrophy 1

Clinical Characteristics
Ocular Features: 

Posterior subcapsular cataracts may be seen at any age, often with striking iridescent opacities in the overlying cortex as well.  These polychromatic lens changes can be diagnostic but are present in only 50% of young adults with myotonic dystrophy.  When present, they are almost always bilateral.  Proximal muscle involvement leads to ptosis, strabismus, weakness of the orbicularis oculi, and sometimes ophthalmoplegia.  Such muscle weakness may lead to exposure keratitis. 

As many as 25% of patients with DM have a pigmentary retinopathy, usually in a butterfly pattern.

A low IOP and even hypotony is sometimes seen.  The mean IOP in a series of 51 patients has been reported as 10.9 compared with 15.4 in controls.  Using ultrasound biomicroscopy, ciliary body detachments were found in at least one quadrant of all eyes.

Systemic Features: 

In the congenital form, hypotonia, generalized weakness, mental retardation and respiratory insufficiency are often present.  There is a great deal of clinical heterogeneity among patients.  Those with mild disease may have only cataracts and mild myotonia with a normal life expectancy.  Those with more severe disease (classical myotonic dystrophy) have these signs plus marked muscle weakness and wasting.  Cardiac conduction defects with secondary arryhthmias are a significant cause of mortality. Such patients tend to become disabled in adulthood.  Symptoms become evident in the second decade or later.  Deep muscle pain is common and can be severe.  Distal muscle weakness usually begins before facial muscle weakness is apparent.  Myotonia often involves the tongue while proximal muscle weakness can cause dysphagia and dysarthria.  Such patients may also suffer respiratory distress. Reproductive fitness is reduced in males who can have gonadal atrophy.  Frontal balding is common.  Some age-related cognitive decline occurs.

Over 60% of patients have a hearing impairment and more than half of these have auditory brainstem response abnormalities.  Vestibular hypesthesia is present in 37.5%.

Genetics

Myotonic dystrophy 1 is an autosomal dominant disorder caused by a trinucleotide (CTG) repeat expansion in a region of the DMPK gene (19q13.2-q13.3).  The number of repeats varies widely and is roughly correlated with severity of disease.  Infants with congenital myotonia usually have the highest number of repeats and have the most severe cognitive deficits.  The number can expand during gametogenesis each generation (resulting in the phenomenon of anticipation) and females generally transmit larger numbers.  Most infants with congenital myotonia are offspring of affected mothers.  Reduced fetal movement and hydramnios are often noted during such pregnancies.

Affected males have few offspring secondary to gonadal atrophy.  Affected heterozygous females, however, do not have the expected ratio of affected offspring because of the dynamic nature of the number of repeats.  The risk of an affected offspring for a nulliparous afflicted female is only 3-9% and she has a 20-40% risk of recurrence after the birth of an affected child.

In a study of sibships with myotonic dystrophy, 58% of offspring were affected when the transmitting parent was male and 63% when the transmitting parent was female.

At least some of the variable transmission risks and clinical heterogeneity may be explained by somatic instability of the CTG repeat numbers.  The degree of instability, moreover, may also be heritable.  Age of onset, for example, is modified by the level of somatic instability.  Further, patients in whom the repeat expands more rapidly develop symptoms earlier. 

A similar disorder, myotonic dystrophy 2 (602668), is caused by a tetranucleotide repeat expansion in the CNBP gene.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

A variety of pharmaceutical agents have been tried for pain management without consistent results.  No treatment improves the muscle weakness.  Cholesterol lowering drugs such as statins should be avoided.  Physical therapy may be helpful.

Cardiac conduction and structural defects are a significant threat even in asymtomatic patients and require constant monitoring for the development of arrythmias.

References
Article Title: 

Inner ear dysfunction in myotonic dystrophy type 1

Balatsouras DG, Felekis D, Panas M, Xenellis J, Koutsis G, Kladi A, Korres SG. Inner ear dysfunction in myotonic dystrophy type 1. Acta Neurol Scand. 2012 Nov 5. doi: 10.1111/ane.12020. [Epub ahead of print].

PubMed ID: 
23121018

Somatic instability of the expanded CTG triplet repeat in myotonic dystrophy type 1 is a heritable quantitative trait and modifier of disease severity

les F, Couto JM, Higham CF, Hogg G, Cuenca P, Braida C, Wilson RH, Adam B, Del Valle G, Brian R, Sittenfeld M, Ashizawa T, Wilcox A, Wilcox DE, Monckton DG. Somatic instability of the expanded CTG triplet repeat in myotonic dystrophy type 1 is a heritable quantitative trait and modifier of disease severity. Hum Mol Genet. 2012 May 16. [Epub ahead of print].

PubMed ID: 
22595968

Incidence and predictors of sudden death, major conduction defects and sustained ventricular tachyarrhythmias in 1388 patients with myotonic dystrophy type 1

Wahbi K, Babuty D, Probst V, Wissocque L, Labombarda F, Porcher R, Becane HM, Lazarus A, Behin A, Laforet P, Stojkovic T, Clementy N, Dussauge AP, Gourraud JB, Pereon Y, Lacour A, Chapon F, Milliez P, Klug D, Eymard B, Duboc D. Incidence and predictors of sudden death, major conduction defects and sustained ventricular tachyarrhythmias in 1388 patients with myotonic dystrophy type 1. Eur Heart J. 2016 Dec 9. pii: ehw569. [Epub ahead of print] PubMed.

PubMed ID: 
27941019
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