respiratory distress

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

Oculopharyngodistal Myopathy

Clinical Characteristics
Ocular Features: 

Progressive ptosis, which may be asymmetric, is an early sign.  Extraocular palsy occurs as well. 

Systemic Features: 

The mean age of onset of this progressive disease is 22 years.  Pharyngeal and distal limb muscles seem to be primarily involved.  Weakness in masseter, facial, and bulbar muscles have been observed but no muscle group seems to be spared.  Atrophy of facial muscles is common and may be pronounced.  There is considerable variability in expression, particularly in the degree of limb weakness which often appears by the fifth decade.  Swallowing difficulties can be severe.  Respiratory weakness may be evident relatively early, even while patients are still ambulatory.  Loss of ambulation most commonly occurs by the third or fourth decade after the onset of first symptoms.  Serum creatine kinase levels are mildly elevated and histologic changes show chronic myopathic changes with rimmed vacuole formation.  No changes have been found in the central or peripheral nervous system. 

Genetics

The causative mutation has not been identified but mutations causing other forms of hereditary myopathy have been ruled out.  Most families are consistent with autosomal dominant inheritance but the pattern in at least one family has suggested a recessive pattern indicating genetic heterogeneity. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Supportive treatment such as physical and respiratory therapies may be helpful but no specific treatment is available for the muscle disease.

References
Article Title: 

Oculopharyngodistal myopathy

Satoyoshi E, Kinoshita M. Oculopharyngodistal myopathy. Arch Neurol. 1977 Feb;34(2):89-92.

PubMed ID: 
836191

Sanfilippo Syndrome (MPS IIIA, B, C, D)

Clinical Characteristics
Ocular Features: 

This form of mucopolysaccharidosis causes little or no corneal clouding.  Abnormal retinal pigmentation can be seen.

Systemic Features: 

Sanfilippo syndrome differs from other forms of mucopolysaccharidoses in the severity of the neurologic degeneration compared to the amount of somatic disease.  Infants usually appear healthy but developmental delay becomes evident by 2 or 3 years of age and physical growth slows.  Deterioration in mental development is progressive and seizures occur in some.  Gait and speech are impaired and by age 10 years patients have severe disabilities.  Behavioral problems including hyperactivity and aggression are often severe.

There is some hepatosplenomegaly, mild coarseness of the facial features, claw hands and mild bony changes such as biconvexity of the vertebral bodies and thick calvaria.  Hirsutism and synophrys are common.  The hair is unusually coarse.  Joints are frequently stiff and more severely affected individuals may have hearing loss.  Diarrhea is frequently a problem and most patients have some airway obstruction and are susceptible to recurrent respiratory infections.  Some patients have cardiovascular problems.

Genetics

MPS III is a lysosomal storage disease and may be caused by mutations in 1 of 4 genes that result in defective enzymes unable to break down mucopolysaccharides (glycosaminoglycans).  MPS IIIA (252900)results from a defect in the heparan sulfate sulfatase gene SGSH (17q25.3), type IIIB (252920)from a defect in the N-acetyl-alpha-D-glucosaminidase gene NAGLU (17q21), type IIIC (252930) from a defect in the acetyl-CoA:alpha-glucosaminide acetyltransferase gene HGSNAT (8p11.1), and type IIID (252940) from a defect in the N-acetylglucosamine-6-sulfatase gene GNS (12q14).  Heparan sulfate is excreted in all types.  Because of their clinical similarities these are discussed as a group in this database.  All are inherited in autosomal recessive patterns.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for the underlying disease.  Therapy is primarily supportive.  A multidisciplinary approach with neurologists, ophthalmologists, audiologists, cardiologists, gastroenterologists, and orthopedists is most likely to result in treatments that can improve quality of life.

References
Article Title: 

Osteogenesis Imperfecta

Clinical Characteristics
Ocular Features: 

Blue sclerae, especially at infancy, is the most visible ocular sign in osteogenesis imperfecta but it is not always present.  It is also often present in normal infants.  In some patients, it is present early but disappears later in life. Some patients have significantly lower ocular rigidity, corneal diameters, and decreased globe length.  Interestingly, the intensity of the blue color in the sclerae does not seem to be correlated with scleral rigidity.

Systemic Features: 

A defect in type I collagen leading to brittle bones and frequent fractures is the systemic hallmark of this group of disorders.  Clinical and genetic heterogeneity is evident. The nosology is as yet not fully established and will likely require more molecular information.  Type I is considered the mildest of the several forms that have been reported.  Relatively minor trauma during childhood and adolescence can lead to fractures while adults have less risk.  Fractures generally heal rapidly without deformities  and with good callous formation in patients with milder disease.  However, those with more serious disease often end up with deformities and bowed bones.

Short stature, hearing loss, easy bruising, and dentinogenesis imperfecta are often seen as well.

Type II is more severe and fractures often occur in utero.  Fractures may involve long bones, skull bones and vertebrae.  At birth the rib case appears abnormally small and the underdeveloped pulmonary system may lead to severe respiratory problems and even death in some newborns.

Genetics

A number of conditions are associated with fragile bones and the classification of these in the early literature is confusing.  More confusion arises from classification schemes based solely on clinical degrees of severity.   

The designation ‘osteogenesis imperfecta’ is most accurately applied to disorders caused by construction defects in type I collagen fibers which are responsible in 90% of affected individuals.  The defect may occur in either the pro-alpha 1 or pro-alpha 2 chains which together form type I collagen.  The responsible genes are COL1A1 (17q21.31) and COL1A2 (7q22.1).  Clinical types I (166200), IIA (166210), III (259420), and IV (166220) map to these two loci.  The inheritance pattern is autosomal dominant.

Mutations in the CRTAP gene (610854; 3p22) cause an autosomal recessive OI-like phenotype classified as type VII while type VIII is an autosomal recessive OI-like disorder secondary to mutations in LEPRE1 (610915; 1p34).  However, these disorders, while clinically sharing some features of true OI, are better designated as separate conditions based on their unique molecular etiologies.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Avoidance of trauma is paramount.   Periodic intravenous administration of pamidronate can increase bone density and reduce the risk of fractures. Oral bisphosphonates do not seem to be beneficial.  Prompt reduction of fractures is important to the prevention of deformities. A multidisciplinary team is important for the treatment and rehabilitation of patients.

References
Article Title: 

Sulfite Oxidase Deficiency

Clinical Characteristics
Ocular Features: 

Dislocated lenses are the only significant ocular features of this disorder.  In one patient the lenses were said to be in normal position at 5.5 months of age but mild nasal subluxation of both lenses was present at 11 months.  In a series of 22 patients, 10 had dislocated lenses and one had spherophakia.  Lens dislocations occur early and maybe even congenitally in some cases as the diagnosis has been made in seven children before one year of age.  On the other hand it is not a consistent sign since the lenses were not dislocated in seven individuals who were examined specifically for this sign.

Systemic Features: 

Outside of the eye, the main features of this disorder are secondary to neurological damage.  Symptoms of irritability, poor feeding, ataxia, and language development may be seen in the first year or two of life.  Respiratory distress can be a feature in neonates.  Hypotonia, dystonia and choreoathetosis may be seen as well.  Seizures (sometimes with opisthotonus) often occur in the first days or weeks of life.  Later, generalized hypertonia and hyperactive reflexes are present.  Global developmental delays occur in nearly 80% of patients.  However, some patients also have a later onset with a milder course indicating that the full range of clinical expression remains to be determined.

Genetics

A number of mutations in the SUOX gene on chromosome 12 (12q13.13) cause this rare autosomal recessive disorder.  Less than 50 cases have been reported worldwide.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Not enough patients have been evaluated for long enough to determine the optimum treatment but low protein diets and restriction of sulfur containing amino acids have been tried with mixed results.

References
Article Title: 

Isolated sulfite oxidase deficiency

Claerhout H, Witters P, Regal L, Jansen K, Van Hoestenberghe MR, Breckpot J, Vermeersch P. Isolated sulfite oxidase deficiency. J Inherit Metab Dis. 2017 Oct 4. doi: 10.1007/s10545-017-0089-4. [Epub ahead of print].

PubMed ID: 
28980090
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