hypotonia

Spinocerebellar Ataxia, Infantile-Onset

Clinical Characteristics
Ocular Features: 

Ocular problems begin by about age 7 years when various degrees of ophthalmoplegia appear.  By the second decade damage to the optic nerves is evident (optic atrophy) leading to severe vision loss.

Systemic Features: 

This mitochondrial DNA depletion syndrome allows normal development in the first year of life.  By 10-18 months of age, muscle weakness and coordination become evident.  Deep tendon reflexes are diminished or absent.  The muscle deficits are relentlessly progressive and by teenage years most individuals are wheelchair-bound.  Generalized seizures are common.  Facial and limb dyskinesia of an athetoid nature is evident to a variable degree.  A sensory polyneuropathy develops in many patients.  Cerebellar atrophy is evident on neuroimaging.

Neurosensory hearing loss may become evident late in the first decade of life.  The amount of hearing loss is progressive, leading eventually to profound deafness.  Some patients experience a complete loss of vestibular caloric responses. 

Most individuals live to adulthood but a severe form of this disease in which liver damage and encephalopathy occur limits the lifespan to about 5 years.

Genetics

This infantile-onset form of spinocerebellar atrophy results from homozygous or compound heterozygous mutations in the C10ORF2 gene (10q24) which encodes the so-called Twinkle and Twinky mitochondrial proteins. Since the Twinkle protein is involved in the production and maintenance of mitochondrial DNA, its malfunction leads to reduced quantities of mtDNA in the liver and CNS but not in skeletal muscle.

Mutations in the C10ORF2 gene affecting the Twinkle protein may be responsible for an autosomal dominant progressive ophthalmoplegia (609286) in which ptosis and cataracts are often found but the more extensive muscle and sensory deficits are often missing.  This is one of the better examples of seemingly unique, allelic phenotypes resulting from different mutations in the same gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported but physical therapy, assistive hearing devices, and low vision aids might be helpful in selected patients.

References
Article Title: 

Infantile onset spinocerebellar ataxia caused by compound heterozygosity for Twinkle mutations and modeling of Twinkle mutations causing recessive disease

Pierce SB, Gulsuner S, Stapleton GA, Walsh T, Lee MK, Mandell JB, Morales A, Klevit RE, King MC, Rogers RC. Infantile onset spinocerebellar ataxia caused by compound heterozygosity for Twinkle mutations and modeling of Twinkle mutations causing recessive disease. Cold Spring Harb Mol Case Stud. 2016 Jul;2(4):a001107. doi: 10.1101/mcs.a001107.

PubMed ID: 
27551684

Williams Syndrome

Clinical Characteristics
Ocular Features: 

Blue irides (77%) and a lacey or stellate pattern (74%) of the iris are characteristic.  The stroma appears coarse with radial or cartwheel striations.  The iris collarette is usually absent or anomalous.  Features of the Peters' anomaly may be present.  The periorbital tissues are described as 'full' and prominent.  Strabismus (usually esotropia) occurs in more than half of patients.  Retinal vessel tortuosity is present in 22% of patients.  Cataracts may be found in younger individuals but are uncommon. Hyperopia is the most common refractive error.  Keratoconus has been described in at least 3 patients.

Systemic Features: 

The phenotype is variable, likely depending upon the size of the deletion.  Cardiovascular disease, primarily hypertension and large vessel stenosis, are among the most important features.  The elastin arteriopathy lead to thickened arterial walls with peripheral pulmonary stenosis and supravalvular aortic stenosis.  The facies is considered unique with bitemporal narrowing, a wide mouth, full lips, malocclusion, small jaw, and prominent earlobes.  The teeth are small and widely spaced.  Connective tissue abnormalities include joint hyperextensibility, hernias, lax skin, hypotonia, and bowel/bladder diverticulae.  Small birth size is common and infants often fail to thrive but at puberty patients can experience a growth spurt.  Ultimate height in adults is usually in the third centile.

Vocal cord anomalies and paralysis can result in a hoarse voice.  A sensorineural hearing loss is common among adults but hyperacusis is often present in young children.

Hypercalcemia and hypercalciuria are common and some (10%) have hypothyroidism.

Most individuals have some cognition difficulties and delays but normal intelligence has also been reported.  Patient personalities consist of anxiety, attention deficit disorder, marked friendliness and a high level of empathy.  Visiospatial construction is often impaired.  Most adults are unable to live independently.

Genetics

This is a deletion syndrome but included in this database because the major features are due to the loss of a single gene (ELN).  The deletion segment consists of 1.4-1.8 Mb at 7q11.23 containing as many as 28 genes.   Most cases occur sporadically but parent-child transmission and affected siblings have been reported.  The recurrence risk is low.

Increased tortuosity of the retinal arterioles is also a feature of Fabry disease (301500) and of a condition known as isolated retinal arteriolar tortuosity (611773, 180000).

Treatment
Treatment Options: 

Feeding issues should be addressed early in infants who fail to thrive.  Early intervention with speech and physical therapy plus special education can be helpful.  Psychological evaluations may help in managing behavioral issues.

Hypertension can often be managed medically but surgery may be required for vascular stenoses.   Hypercalcemia and hypothyroidism often respond to medical therapy. Strabismus, vessel narrowing, and valvular malfunctions can be treated surgically.

References
Article Title: 

The iris in Williams syndrome

Holmstrom G, Almond G, Temple K, Taylor D, Baraitser M. The iris in Williams syndrome. Arch Dis Child. 1990 Sep;65(9):987-9.

PubMed ID: 
2221973

Ocular findings of Williams' syndrome

Hotta Y, Kishishita H, Wakita M, Inagaki Y, Momose T, Kato K. Ocular findings of Williams' syndrome. Acta Paediatr Scand. 1990 Aug-Sep;79(8-9):869-70.

PubMed ID: 
2239289

Congenital Disorder of Glycosylation, Type Ia

Clinical Characteristics
Ocular Features: 

Strabismus, roving eye movements (and nystagmus), and visual inattention are found in nearly all patients. Esotropia with defective abduction seems to be the most common oculomotor finding and may be present at birth.  Cataracts, ocular colobomas, oculomotor apraxia, disc pallor, and glaucoma have also been reported.  Vision is always subnormal. Reports of ocular disease before modern genotyping are not specific to the subtypes of CDG I now recognized.

This is a congenital, progressive disorder of photoreceptor degeneration with a later onset of progressive pigmentary retinopathy.  It is described in some cases as a typical retinitis pigmentosa.  The ERG is abnormal in all patients even if the pigmentary pattern is atypical for RP.  Rod responses are usually absent while the cone b-wave implicit time is delayed.  The degree of photoreceptor damage is variable, however.  Extended retinal function among younger patients suggest that the ‘on-pathway’ evolving synapses in the outer plexiform layer among photoreceptors, bipolar cells, and horizontal cells is severely dysfunctional.

Systemic Features: 

This is a multisystem disorder, often diagnosed in the neonatal period by the presence of severe encephalopathy with hypotonia, hyporeflexia, and poor feeding.  Failure to thrive, marked psychomotor retardation, delayed development, growth retardation, and ataxia become evident later in those who survive.  Cerebellar and brainstem atrophy with a peripheral neuropathy can be demonstrated during late childhood.  Some older patients have a milder disease, often with muscle atrophy and skeletal deformities such as kyphoscoliosis and a fusiform appearance of the digits.  Maldistribution of subcutaneous tissue is often seen resulting in some dysmorphism, especially of the face.  Hypogonadism and enlargement of the labia majora are commonly present.  Some patients have evidence of hepatic and cardiac dysfunction which together with severe infections are responsible for a 20% mortality rate in the first year of life.

Genetics

This is one of a group of genetically (and clinically) heterogeneous autosomal recessive conditions caused by gene mutations that result in enzymatic defects in the synthesis and processing of oligosaccharides onto glycoproteins. This type (Ia) is the most common.   The mutation lies in the PMM2 gene (16p13.2).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Most children require tube feeding with nutritional supplements.  The risk of systemic infections is high.  Those patients who survive into the second decade and beyond may require orthopedic procedures and are confined to wheelchairs.  Physical, occupational, and speech therapy along with parental support are important.

References
Article Title: 

Joubert Syndrome and Related Disorders

Clinical Characteristics
Ocular Features: 

Ocular findings like systemic features are highly variable both within and between families.  Vision can be normal but in other patients it is severely reduced to the range of 20/200.  The pupils may respond sluggishly or even paradoxically to light.  ERG recordings have been reported to be normal in some patients, but absent or reduced in others.  The fundus appearance is often normal but in other individuals the pigmentation is mottled, the retinal arterioles are attenuated, and the macula has a cellophane maculopathy.  Drusen and colobomas are sometimes seen in the optic nerve while occasional patients have typical chorioretinal colobomas.  The eyebrows are often highly arched.

The oculomotor system is frequently involved.  Apraxia to some degree is common with most patients having difficulty with smooth pursuit and saccadic movements.  Compensatory head thrusting is often observed.  A pendular nystagmus may be present while esophoria or esotropia is present in many patients.

Systemic Features: 

There is a great deal of clinical heterogeneity in this group of ciliary dyskinesias.  Developmental delays, cognitive impairment, truncal ataxia, breathing irregularities, and behavioral disorders are among the more common features.  Hyperactivity and aggressiveness combined with dependency require constant vigilance and care.  Postaxial polydactyly is a feature of some cases.  Hypotonia is evident at birth.  Liver failure and renal disease develop in many individuals.  Neuroimaging of the midbrain-hindbrain area reveals agenesis or some degree of dysgenesis of the vermis with the 'molar tooth sign' in the isthmus region considered to be a diagnostic sign.  The fourth ventricle is usually enlarged while the cerebellar hemispheres may be hypoplastic.

The facies features are said to be distinctive in older individuals.  The face appears long with frontal prominence due to bitemporal narrowing, the nasal bridge and tip are prominent, the jaw is prominent, the lower lip protrudes, and the corners of the mouth are turned down.

Genetics

This is a clinically and genetically heterogeneous group of disorders with many overlapping features.  Most disorders in this disease category, known as JSRD, are inherited in an autosomal recessive pattern.  Mutations in at least 34 genes have been identified.  One, OFD1 (300804), is located on the X chromosome (Xp22.2).

There are significant clinical similarities to Meckel syndrome (249000) and Smith-Lemli-Opitz syndrome (270400).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is mostly for specific symptoms such as respiratory distress, renal disease, speech and physical therapy, low vision, and hepatic failure.

References
Article Title: 

Joubert Syndrome: Ophthalmological Findings in Correlation with Genotype and Hepatorenal Disease in 99 Patients Prospectively Evaluated at a Single Center

Brooks BP, Zein WM, Thompson AH, Mokhtarzadeh M, Doherty DA, Parisi M, Glass IA, Malicdan MC, Vilboux T, Vemulapalli M, Mullikin JC, Gahl WA, Gunay-Aygun M. Joubert Syndrome: Ophthalmological Findings in Correlation with Genotype and Hepatorenal Disease in 99 Patients Prospectively Evaluated at a Single Center. Ophthalmology. 2018 Jul 25. pii: S0161-6420(18)30686-9. doi: 10.1016/j.ophtha.2018.05.026. [Epub ahead of print].

PubMed ID: 
30055837

Ophthalmological findings in Joubert syndrome

Sturm V, Leiba H, Menke MN, Valente EM, Poretti A, Landau K, Boltshauser E. Ophthalmological findings in Joubert syndrome. Eye (Lond). 2010 Feb;24(2):222-5.

PubMed ID: 
19461662

Gurrieri Syndrome

Clinical Characteristics
Ocular Features: 

Tapetoretinal degeneration has been described in several patients.  Some patients have keratoconus with lens and corneal opacities.  Visual acuities have not been reported.  The full ocular phenotype must be considered unknown since most patients have not had full ophthalmic evaluations.

Systemic Features: 

Features of an osteodysplasia are among the most striking in this syndrome.  Short stature, brachydactyly, delayed bone age, osteoporosis, and hypoplasia of the acetabulae and iliac alae are usually present.  Birth weight is often low.  Joints may be hyperflexible as part of the generalized hypotonia. The eyes are deep-set, the nasal bridge is prominent, the midface is flat, and the supraorbital ridges are prominent giving the face a rather coarse look.  Prognathism with a prominent lower lip and dental malocclusion reinforce this appearance.  Seizures beginning in early childhood may be difficult to control.  Most patients have severe psychomotor retardation and never acquire speech.

Genetics

The genetics of this familial disorder remain unknown.  No locus or mutation has been identified but one patient had an absent maternal allele of the proximal 15q region as found in Angelman syndrome.

Orofaciodigital syndrome IX (258865) is another autosomal recessive syndrome sometimes called Gurrieri syndrome.  In Gurrieri’s original description of two brothers, chorioretinal lacunae, similar to those seen in Aicardi syndrome (304050), were present.  The systemic features are dissimilar, however.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Sengers Syndrome

Clinical Characteristics
Ocular Features: 

This is a mitochondrial DNA depletion syndrome in which congenital cataracts are the hallmark ocular feature.  The bilateral lens opacification is usually total at birth or within the first few weeks of life as manifested by leucocoria. Lens extraction is necessary within the first 6 months of life but visual rehabilitation is nearly always compromised postoperatively by nystagmus and strabismus.  In one series only one eye recovered to 20/40 but the average postoperative acuity was in the range of 20/200 and virtually all students require special education in schools for the visually impaired.  Axial myopia is common with most patients having myopic fundus changes and requiring less than +10 diopters of aphakic correction.  Pale optic disks and a pigmentary retinopathy were noted among 8 of 18 eyes in one series.  Mild and inconsistent dyschromatopsia has been reported in a few patients.  The ERG sometimes shows diminished rod and cone function.

Systemic Features: 

Hypertrophic cardiomyopathy is often diagnosed within a fews days after birth but 40% may escape detection until the second or third decade of life.  It is usually progressive and often fatal in the neonatal period.  Myopathy involves both cardiac and skeletal muscles.  Generalized hypotonia, exercise intolerance, and delayed motor development are important features in the majority of patients.  Metabolic lactic acidosis occurs with relatively minimal excercise.  Skeletal muscle biopsies show ragged-red fibers with combined deficiencies of mitochondrial complexes I, III, and IV along with severe depletion of mtDNA.  Increased urine levels of 3-methylglutaconic have been reported.

The central nervous system is usually not involved and mental development is normal if lactic acidosis is controlled.  However, several children with mental retardation have been reported.

Genetics

Homozygous or compound heterozygous mutations in AGK (7p34), a lipid metabolism gene, are responsible for this condition.  There is considerable variation in the severeity of the phenotypic features but no ocular or cardiac disease has been found in heterozygotes. 

The same gene was found to be mutated in an autosomal recessive congenital cataract (614691) in a single reported sibship. Thorough systemic evaluation found no evidence of cardiac and skeletal muscle disease.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Surgical removal of cataracts may be indicated.

References
Article Title: 

Lack of the mitochondrial protein acylglycerol kinase causes Sengers syndrome

Mayr JA, Haack TB, Graf E, Zimmermann FA, Wieland T, Haberberger B, Superti-Furga A, Kirschner J, Steinmann B, Baumgartner MR, Moroni I, Lamantea E, Zeviani M, Rodenburg RJ, Smeitink J, Strom TM, Meitinger T, Sperl W, Prokisch H. Lack of the mitochondrial protein acylglycerol kinase causes Sengers syndrome. Am J Hum Genet. 2012 Feb 10;90(2):314-20.

PubMed ID: 
22284826

Canavan Disease

Clinical Characteristics
Ocular Features: 

Optic atrophy is the primary and perhaps only ocular manifestation of Canavan disease.  Acuity levels have not been reported but it has been noted that some infants and young children with early onset severe disease are able to track targets.  The ocular phenotype has not been well delineated.

Systemic Features: 

The clinical diagnosis of Canavan disease is suggested when the triad of hypotonia, macrocephaly and head lag is present.  It is a progressive form of spongy degeneration of the central nervous system but its onset, course, and severity are variable.

The disease is often evident before 6 months of age and survival is limited to a few months or years in infants with such early onset.  Such patients have the most severe and rapidly progressive disease.  It is noteworthy that, even though such infants do not achieve normal milestones such as sitting and standing, they do often interact socially by laughing, smiling, and reaching for objects.  Most young children are quiet and apathetic but some become irritable and develop spasticity as they grow.  CNS damage is evident as leukodystrophy on neuroimaging studies but this may not be present in later onset, milder forms of the disease.         

Other individuals may have a later and milder juvenile onset of symptoms and may present with delayed speech or motor development late in the first decade.  They often attend regular school but may benefit from tutoring and speech therapy.  They may live to adolescence or early adulthood.  Maldevelopment of the organ of Corti is responsible for hearing deficits in some children.

Genetics

Canavan disease is an autosomal recessive disorder resulting from homozygous or compound heterozygous mutations in the gene (ASPA) located at 17p13.2 encoding the enzyme aspartoacylase.  N-acetylaspartic acid (NAA) levels are usually elevated in urine.  However, because the levels of NAA can vary depending on the severity of clinical disease, gene testing provides a more reliable diagnosis. 

The carrier frequency is high among members of the Ashkenazi Jewish population.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Antiepileptic drugs can be helpful.  Augmented feeding (gastric tubes)may be needed to maintain nutrition, while physical therapy and exercise may prevent contractures.  Speech therapy and low vision aids might be of benefit. Rare patients with a hearing deficit should be evaluated for possible benefit of hearing aids.

References
Article Title: 

Oculomotor Apraxia

Clinical Characteristics
Ocular Features: 

This is a disorder of impaired smooth ocular pursuit movements.  Voluntary horizontal eye movements are absent or defective while vertical gaze and random eye movements are usually retained.  Patients learn early to compensate by sharply turning the head in a jerky, thrusting fashion.  The head turn often overshoots because the eyes tend to deviate in the opposite direction as a result of the vestibular reflex.  Blinking is also sometimes employed to initiate eye movements.  The condition is likely congenital in onset but it is not progressive.  In fact, the ability to look from side to side improves in at least some patients.

Systemic Features: 

The small number of reported patients has limited description of the full phenotype but this seems to be a generalized neurological disorder.  Patients have been reported with global developmental delay, hypotonia, cognitive delays, ataxia/clumsiness, and speech difficulties.  Neuroimaging may reveal abnormalities in various brain stuctures including the cerebellum, cerebrum, vermis, and corpus callosum in 40% of patients.       

Genetics

The genetics of isolated oculomotor apraxia is unknown since no responsible mutation has been identified.  However, familial cases are known, including twins and sibling offspring of consanguineous matings, as well as multigenerational cases.  This condition may be genetically heterogeneous since autosomal recessive and autosomal dominant transmission patterns seem equally likely.  It may also be possible that the Cogan-type oculomotor apraxia is not a isolated entity but simply an associated sign as part of more generalized neurological disease.

Oculomotor apraxia may also be seen in ataxia-telangiectasia (208900), ataxia with oculomotor apraxia 1 (208920), ataxia with oculomotor apraxia 2 (602600) and in Gaucher disease (203800).  It may be the presenting sign in the latter disease.  

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Nosological delineation of congenital ocular motor apraxia type Cogan: an observational study

Wente S, Schroder S, Buckard J, Buttel HM, von Deimling F, Diener W, Haussler M, Hubschle S, Kinder S, Kurlemann G, Kretzschmar C, Lingen M, Maroske W, Mundt D, Sanchez-Albisua I, Seeger J, Toelle SP, Boltshauser E, Brockmann K. Nosological delineation of congenital ocular motor apraxia type Cogan: an observational study. Orphanet J Rare Dis. 2016 Jul 29;11(1):104. doi: 10.1186/s13023-016-0486-z.

PubMed ID: 
27473762

GM3 Synthase Deficiency

Clinical Characteristics
Ocular Features: 

Optic atrophy is the primary ocular feature in this disorder.  ERG amplitudes and retinal pigmentation are normal.  Visual impairment is pronounced with no reactions to threatening visual stimuli.  Eye movements are random and uncoordinated.  Optic atrophy is present but no retinal abnormalities have been reported.

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.

Hypo- and hyperpigmented skin macules in a 'salt and pepper' pattern, have been described.  These vary from 2-5 mm in size and are located primarily on the extremities.  These are found among children older than 3 years of age and some parents have reported that the hyperpigmentation may decrease after many years.  No such lesions were found in mucosal tissue.        

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: 

Congenital Disorder of Glycosylation, Type Ij

Clinical Characteristics
Ocular Features: 

Bilateral cataracts are present at birth.  Nystagmus, strabismus, and long eyelashes have been reported.

Systemic Features: 

This is a disorder of glycosylation important to the formation of glycoproteins and glycolipids.  Neurological signs such as tremor, clonus, and muscle fasiculations may be seen soon after birth.  Other neurological abnormalities eventually include psychomotor retardation, seizures, mental retardation, hyperexcitabilty, and ataxia.  Failure to thrive and feeding difficulties are evident early.  Progressive microcephaly is a feature.  Liver dysfunction can lead to coagulopathy and hypoproteinemia with hepatomegaly is sometimes present.  Some patients have facial anomalies, inverted nipples, and subcutaneous fat pads.  The MRI may show areas of brain atrophy, ischemia, and focal necrosis.

Longevity is limited with 2 of 3 reported patients dying within 2 years of life.

Genetics

This is a rare autosomal recessive disorder resulting from mutations in DPAGT1 (11q23.3) resulting in defective N-glycosylation.  There are numerous other types of glycosylation defects with variations in the clinical manifestations.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment consists of fluid and caloric intake management.  Hypoproteinemia and coagulation defects may respond to oral mannose administration.

References
Article Title: 

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