irritability

Combined Oxidative Phosphorylation Deficiency 32

Clinical Characteristics
Ocular Features: 

Ocular signs are common but variable.  Patients may not make eye contact and sometimes have disconjugate eye movements.  Strabismus (usually exotropia) and nystagmus or often present.

Systemic Features: 

Six patients from 4 unrelated families of mixed ethnic backgrounds have been reported.  Infants within the first 4 to 6 months of life had evidence of developmental delay and neurodevelopmental regression.  Poor feeding and breathing difficulties are often noted in this period.  Other later signs are axial hypotonia, abnormal movements such as tremor, spasticity, hyperkinetic movements, dystonia with eventual regression of milestones.  Joint contractures and kyphoscoliosis may develop. 

Microcephaly was noted in several infants and brain imaging in all patients reveals abnormal T2- weighted signals in the brainstem and specifically in the basal ganglia.  Decreased activity in muscle mitochondrial respiratory complexes I, III, and IV has been documented.  Lactate may be increased in serum and the CSF.  Postmortem studies show brain vascular proliferation and gliosis in basal structures.

Genetics

Homozygous or compound heterozygous mutations in MRPS34 (16p13.3) are the basis for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome

Lake NJ, Webb BD, Stroud DA, Richman TR, Ruzzenente B, Compton AG, Mountford HS, Pulman J, Zangarelli C, Rio M, Bodaert N, Assouline Z, Sherpa MD, Schadt EE, Houten SM, Byrnes J, McCormick EM, Zolkipli-Cunningham Z, Haude K, Zhang Z, Retterer K, Bai R, Calvo SE, Mootha VK, Christodoulou J, Rotig A, Filipovska A, Cristian I, Falk MJ, Metodiev MD, Thorburn DR. Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome. Am J Hum Genet. 2017 Aug 3;101(2):239-254.

PubMed ID: 
28777931

GM3 Synthase Deficiency

Clinical Characteristics
Ocular Features: 

Profound optic atrophy is the primary ocular feature in this disorder.  ERG amplitudes are normal.  Visual impairment is pronounced with no reactions to environmental stimuli but it is not possible to determine how much of this is due to general CNS disease.  Eye movements are random and uncoordinated. 

Systemic Features: 

Infants may appear normal at birth but within a few months develop signs of developmental stagnation with onset of tonic-clonic seizures.  Irritability, poor feeding, vomiting and failure to thrive are important features.  Generalized hypotonia is evident but lower limb deep tendon reflexes may be present.  Normal developmental milestones are never achieved and patients are unresponsive to their environment.  Older individuals develop non-purposeful choreothetoid movements.  The EEG shows multifocal epileptiform discharges and brain MRIs show diffuse atrophy in older patients.         

Genetics

This is an autosomal recessive disorder secondary to homozygous mutations in (ST3GAL5) (2p11.2) encoding sialytransferase (SIAT9).

The nonsense mutation results in a deficiency of functional GM3 synthase important in the utilization of lactosylceramide necessary for the production of downstream gangliosides.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no known treatment for the enzyme deficiency.  Seizures respond poorly to anti-epileptic medications.

References
Article Title: 

Blue Diaper Syndrome

Clinical Characteristics
Ocular Features: 

A single patient has been reported with microcornea, optic nerve hypoplasia, and 'abnormal' eye movements.  The full ocular phenotype is unknown but 'visual problems' are sometimes mentioned in other reports.

Systemic Features: 

Nephrocalcinosis and blue urine are the major systemic manifestations of blue diaper syndrome.  Symptoms of fever, constipation, poor weight gain, failure to thrive, and irritability can also be part of the syndrome.

Genetics

This is considered an autosomal recessive disorder although an X-linked defect cannot be ruled out since reported patients have been male.  Parental consanguinity is present in some families.  Nothing is known about the mutation or its locus.  Intestinal transport of tryptophan is defective and bacterial degradation results in excessive indole production.  Oxidation in the urine to indigo blue results in the characteristic discoloration.        

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Restriction of dietary tryptophan has been suggested.

References
Article Title: 

Niemann-Pick Disease, Types A and B

Clinical Characteristics
Ocular Features: 

Affected infants usually develop prominent cherry red spots during the first 12 months of life and the entire retina has an ‘opaque’ appearance.  Intracellular lipid accumulation has been seen in retinal neurons, amacrine cells, retinal pigment epithelial cells, and receptors.  The cornea has stromal haziness.  The lens has a brownish coloration on the anterior surface with white spots on the posterior capsule.  Lens opacification seems to progress.

Vision in the first year of life is likely normal as infants have normal fixation, pupillary reactions, and following movements with no nystagmus.  However, by about 2 years of age visual responsiveness may be lost.

Systemic Features: 

Both the age of onset of neurological symptoms and the rate of progression are highly variable. Type A, known as the infantile form, is the more severe disease with onset by 6 months of age with rapid progression and few patients survive beyond three years of age.  Neonates seem to develop normally for the first 6 months but then become irritable, fail to thrive and feed poorly.  Hepatosplenomegaly is usually the first physical sign.  Hypotonia and pulmonary infections are common.  These patients never achieve normal developmental milestones such as sitting, walking or crawling and the neurodegeneration is relentless from this point with the median age at death 21 months, usually from respiratory disease.

The less severe form of Niemann-Pick disease, type B, has a later onset and slower course.  Such patients have widespread visceral disease affecting liver, spleen and lungs with hyperlipidemia but few neurologic symptoms and often survive into adulthood.  Mutations in the same gene are involved, however.  

Other rare cases have intermediate disease and some have proposed these be classified as types E and F but the phenotypes have not been well characterized.  The benefits of such a classification system are questionable as all result from mutations in the same gene simply illustrating the range in the clinical spectrum.

Sphingomyelin and other lipids accumulate in cells of various types including neurons and reticuloendothelial cells accounting for the hepatosplenomegaly and neurodegeneration.  Sphingomyelinase deficiency can be demonstrated in leukocytes and cultured fibroblasts.

Genetics

This is an autosomal recessive neurodegenerative disorder resulting from homozygous mutations in SMPD1 (11p15.4-p15.1) encoding sphingomyelin phosphodiesterase-1.  This recessive gene has an unusual biology.  Only the maternally inherited allele is active in the homozygous condition.  Such parent-specific gene activation is called gene imprinting.

Types A and B are allelic disorders.  

Niemann-Pick diseases designated types C1 and D (257220) are caused by mutations in the NPC1 gene (18q11-q12) and type C2 (607625)  from mutations in the NPC2 gene (14q24.3).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Enzyme replacement therapy trials are underway.  Amniotic membrane, bone marrow, and stem cell transplantation have been tried with some improvement in visceral disease but the results are mixed and await further studies.

References
Article Title: 

Glaucoma, Congenital Primary A

Clinical Characteristics
Ocular Features: 

This may be the most common type of early (infantile, congenital) glaucoma.  Elevated intraocular pressure may be present at birth but sometimes is not evident until the first year of life or in some cases even later.  Irritability, photophobia, and epiphora are early signs.  The globe is often buphthalmic, the cornea is variably cloudy, and breaks in the Descemet membrane (Haab striae) may be present.  Frequently the iris root is inserted anteriorly in the region of the trabecular meshwork.  The anterior chamber often appears abnormally deep.  Early reports of a membrane covering the angle structures have not been confirmed histologically.  The mechanism causing elevated IOP seems to be excessive collagen tissue in the anterior chamber angle that impedes normal aqueous outflow.   The pressure is usually in the range of 25-35 mmHg but this is variable as the course can be intermittent.  It should be considered a bilateral disease although about one-fourth of patients have only unilateral elevations of pressure even though trabecular abnormalities are present.

Optic cupping may begin temporally but the more typical glaucomatous cupping eventually occurs.

Systemic Features: 

No consistent systemic abnormalities are associated with primary congenital glaucoma.  However, it is important to note that glaucoma is a feature of many congenital malformation syndromes and chromosomal aberrations.

Genetics

Congenital glaucoma of this type can result from both homozygous (25%) and compound heterozygous mutations (56%) in the CYP1B1 gene on chromosome 2 (2p22-p21) which codes for cytochrome P4501B1.

Evidence from many sources suggests that congenital glaucoma of this type is an autosomal recessive disorder. Parental consanguinity is common, the segregation ratio is approximately 25%, and the occurrence of congenital glaucoma among all offspring of two affected parents can be cited as support for this mode of inheritance.  Many cases occur sporadically but this is consistent with expectations in small human sibships.  Curiously, though, males are affected more often than females.

Another autosomal recessive infantile (congenital) glaucoma (600975), GLC3 or type B, is caused by mutations in GLC3B located at 1p36.2-p36.1.  A third locus at 14q24.3 has also been proposed  for GLC3, type C.  Autosomal recessive primary congenital glaucoma (so-called) type D (613086) is caused by a mutation in LTBP2 located at 14q24 near the GLC3C locus and heterozygous mutations in TEK are responsible for type E (617272).

Other modes of inheritance have been described and, for now, this form of glaucoma, like others, has to be considered a genetically and clinically heterogeneous disorder pending additional genotyping.  Early onset glaucoma is also a feature of numerous malformation and chromosomal disorders.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Some of the usual glaucoma drugs are ineffective as a result of obstruction to aqueous flow through the trabecular meshwork so that surgical treatment is the therapy of choice in most cases.   Monitoring of axial length has been proposed as helpful in gauging the effectiveness of pressure control.  In some patients the pressure normalizes spontaneously. 

It is important in the evaluation of patients with glaucoma that systemic evaluations be done because of the frequent syndromal associations.

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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