hypertrophic cardiomyopathy

LEOPARD Syndrome

Clinical Characteristics
Ocular Features: 

Ocular hypertelorism is a characteristic of all forms of the LEOPARD syndrome.  The lid fissures may be downward slanting.  Combined with the inverted triangle facies, the appearance is similar to that of the Noonan syndrome (163950).

Systemic Features: 

This is a multisystem disorder manifest in skin, heart, skeletal, genital, neurologic and auditory systems.  Generalized lentiginosis is characteristic but they may not be present until age 4 or 5 years following the appearance of cafe-au-lait spots.  Some patients have patchy scalp hair loss.  The facies bears some resemblance to the Noonan syndrome but usually without the short, webbed neck.  Sensorineural hearing loss is found in 20% of individuals.  Cardiac conduction defects, pulmonic stenosis, and hypertrophic cardiomyopathy are often (85%) present.  Cognitive defects are present in 30% of patients and some individuals have been described as mentally retarded.  Juvenile behavior may be evident in the presence of normal intelligence.  Hypospadias, cryptorchidism, and gonadal infantilism have been seen in some patients.  The ears are often malformed (87%).  Thoracic skeletal anomalies have been described in 75% of patients.  Although somatic growth is described as slow, short stature is present in less than half of patients.

Rare patients without lentigines are said to resemble the Noonan syndrome (163950) in appearance.

Genetics

Heterozygous mutations in the PTPN11 gene (12q24) are most frequently responsible for this autosomal dominant disorder.  The same gene is mutated in more than half of patients with the Noonan syndrome (NS1)(163950) with which it is allelic.  Other mutations that cause what is called LEOPARD syndrome are RAF1 and BRAF.

Other types of LEOPARD syndrome such as LEOPARD syndrome 2 (611554) are far more rare but also share mutations with Noonan syndrome (RAF1 mutations in Noonan syndrome 5) (611553) and LEOPARD syndrome 3 (613707) with mutations in BRAF similar to that seen in NS7 (613706).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Assistive hearing devices, especially cochlear implants, may be helpful.  Special education can be of value in more mildly affected individuals.Treatment of cryptorchidism is similar to that of other children.

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

Friedreich Ataxia 1

Clinical Characteristics
Ocular Features: 

Nystagmus and optic atrophy are important ocular signs.  The visual pathway, both anterior and posterior, is consistently involved and field defects are common even though many patients are asymptomatic.  OCT usually shows a reduced nerve fiber layer secondary to loss of axons.  About half of patients have abnormal visual evoked potentials.  A few patients experience a sudden loss of central vision during the second decade of life.

Systemic Features: 

Friedreich ataxia is a progressive neurodegenerative disorder with onset before puberty.  The spinocerebellar tracts, dorsal columns, pyramidal tracts, cerebellum, medulla, and optic radiation, may all be involved.  The outstanding symptom is ataxia with impairment of gait and weakness in the limbs.  Muscle weakness, extensor plantar responses, and absent lower limb reflexes are usually present.  Dysarthria is usually notable.  Sensory signs include impairment of position and vibratory senses.  'Twitching' in limbs and digits is often noted and 'restless leg syndrome' is common.

Secondary changes include pes cavus, scoliosis, and hammer toe.  Cardiac disease is frequently present and heart failure is the most common cause of death.  Most patients have hypertrophic cardiomyopathy with characteristic EKG changes and some have subaortic stenosis as part of the hypertrophied myocardium.  Diabetes mellitus is present in 20-25%.  Some hearing loss occurs in more than 10% of individuals.

Most patients require a wheelchair within 15 years of disease onset and the mean age of death is about 36 years.

Rare patients with a later onset of FRDA retain lower limb deep tendon reflexes.

Genetics

Homozygous mutations in FXN (9p21.11) are responsible for Friedreich ataxia.  The most common DNA abnormality is a GAA trinucleotide repeat expansion in intron 1.  The number of repeats in patients is 70 to more than 1000 compared with 5-30 in normal individuals.  FXN encodes the mitochondrial protein frataxin.

About 2% of individuals have point mutations in FXN instead of trinucleotide repeats.

Some of the phenotypic variations may be explained by differences in the number of GAA repeats.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is largely directed at symptoms including speech and physical therapy and mobility assistive devices. Scoliosis may require surgical intervention.

References
Article Title: 

Visual system involvement in patients with Friedreich's ataxia

Fortuna F, Barboni P, Liguori R, Valentino ML, Savini G, Gellera C, Mariotti C, Rizzo G, Tonon C, Manners D, Lodi R, Sadun AA, Carelli V. Visual system involvement in patients with Friedreich's ataxia. Brain. 2009 Jan;132(Pt 1):116-23.

PubMed ID: 
18931386

Friedreich ataxia: an overview

Delatycki MB, Williamson R, Forrest SM. Friedreich ataxia: an overview. J Med Genet. 2000 Jan;37(1):1-8. Review.

PubMed ID: 
10633128

Danon Disease

Clinical Characteristics
Ocular Features: 

The ocular features of Danon disease are less well known than the systemic manifestations and are as yet not fully delineated likely because not all patients have visual symptoms or fundus changes.  The most commonly described fundus abnormalities are pigmentary changes variously called a peripheral pigmentary retinopathy or a pigmentary atrophy in some cases.   Changes in pigmentation may be mild in both affected males and carrier females, but are generally more severe in males.  A bulls-eye maculopathy and color vision deficiencies have been described.  Loss of visual acuity is variable and may lead to symptoms before myopathy is evident.  Vision loss is usually progressive and may be reduced to hand motions.  OCT shows thinning of the photoreceptor and RPE layers.  The full field ERG is reduced in amplitude consistent with a generalized cone-rod dystrophy.

Systemic Features: 

This disorder, originally believed to be a type of glycogen storage disease, is actually a form of autophagic vacuolar myopathy.    The characteristic vacuoles are found in muscle cytoplasm surrounded by sarcolemmal proteins and basal lamina.  The primary extraocular disease occurs in the myocardium although skeletal muscle may also be involved.  Intellectual disability is a variable and inconsistent feature.  

Cardiac rhythm abnormalities are common and include AV nodal block, atrial fibrillation, and Wolff-Parkinson-White EKG findings.  Hypertrophic cardiomyopathy (and sometimes dilated cardiomyopathy) with primary involvement of the left ventricle is common.  Symptoms typically occur in males before the age of 20 years and somewhat later in females.

Some patients have muscular weakness and exercise intolerance.  Diagnosis can be made when the characteristic vacuoles are present in a muscle biopsy but their absence does not rule out the diagnosis.

Genetics

This is an X-linked dominant disorder caused by mutations in LAMP2 (Xp24).  Females are generally less severely affected than males. Most men with Danon disease have some intellectual disability as well as skeletal myopathy but these features are found in less than half of affected women.  

Pedigree: 
X-linked dominant, father affected
X-linked dominant, mother affected
Treatment
Treatment Options: 

No known treatment is available for the ocular disease.  Transplantation can be an effective treatment for the cardiomyopathy which can be lethal even in adolescents.

References
Article Title: 

Cardiac arrhythmias in patients with Danon disease

Konrad T, Sonnenschein S, Schmidt FP, Mollnau H, Bock K, Ocete BQ, Munzel T, Theis C, Rostock T. Cardiac arrhythmias in patients with Danon disease. Europace. 2016 Oct 14. pii: euw215.

PubMed ID: 
27742774

Cone-rod dystrophy in Danon disease

Brodie S. Cone-rod dystrophy in Danon disease. Graefes Arch Clin Exp Ophthalmol. 2012 Mar 10. [Epub ahead of print].

PubMed ID: 
22407291

Microphthalmia, Syndromic 7

Clinical Characteristics
Ocular Features: 

Microphthalmia and rarely clinical anophthalmia are the ocular hallmarks of this disorder.  Corneal leukomas and some degree of sclerocornea are usually present as well.  Orbital cysts have been observed.  Other less consistent findings include iridocorneal adhesions, glaucoma, microcornea, cataracts, aniridia, persistence of the anterior hyaloid artery and other vitreous opacities, and patchy hypopigmentation of the RPE.

Systemic Features: 

The skin on the nose, cheeks and neck has linear red rashes and scar-like lesions.  Biopsy of these has revealed smooth muscle hemartomata rather than simple dermal aplasia.  There may be some healing of the skin defects.  The corpus callosum is sometimes absent.  Diaphragmatic hernias are often present.  Cardiac abnormalities include hypertrophic cardiomyopathy, arrhythmias, and septal defects.   Preauricular pits and hearing loss have been found in some patients.  Patients may be short in stature and some have nail dysplasia.  GU and GI anomalies may be present.

Genetics

This is an X-linked dominant disorder with lethality in the hemizygous male.  Many patients (79%) have interstitial deletions of the Xp22.2 region of the X chromosome.  Sequence analysis of this region has revealed heterozygous point mutations in the HCCS gene (Xp22.2) in numerous other patients.  In several additional cases deleterious mutations have been found in the X-linked COX7B gene.  However, familial occurrence is uncommon.  X chromosome inactivation may be skewed with the abnormal X being inactive in virtually all cases. Several 46 XX males with this syndrome have been described.

Goltz syndrome (305600), also called focal dermal hypoplasia, may have similar skin and ocular findings but the limb anomalies are not found in the disorder described here.  Goltz syndrome (305600) is the result of mutations in PORCN at another locus on the X chromosome and is thus unrelated.

Other X-linked dominant disorders with lethality in hemizygous males and abnormalities in skin and the eye are Incontinentia pigmenti (308300) and Aicardi syndrome (304050).  The skin lesions and ocular anomalies are dissimilar to those in MLS and they often have far more severe CNS abnormalities.   Further, the mutation causing Aicardi is in the NEMO (IKBKG) gene at another location on the X chromosome.

Pedigree: 
X-linked dominant, mother affected
Treatment
Treatment Options: 

Treatment is organ-specific with repair of septal defects and diaphragmatic hernias.  Progressive orbital prosthetics should be considered in patients with blind, microphthalmic and clinically anophthalmic eyes.

References
Article Title: 

Microphthalmia with linear skin defects syndrome in a mosaic female infant with monosomy for the Xp22 region: molecular analysis of the Xp22 breakpoint and the X-inactivation pattern

Ogata T, Wakui K, Muroya K, Ohashi H, Matsuo N, Brown DM, Ishii T, Fukushima Y. Microphthalmia with linear skin defects syndrome in a mosaic female infant with monosomy for the Xp22 region: molecular analysis of the Xp22 breakpoint and the X-inactivation pattern. Hum Genet. 1998 Jul;103(1):51-6. Review.

PubMed ID: 
9737776

Noonan Syndrome

Clinical Characteristics
Ocular Features: 

Noonan syndrome has prominent anomalies of the periocular structures including downward-slanting lid fissures, hypertelorism, epicanthal folds, high upper eyelid crease, and some limitation of ocular mobility most commonly of the levator.  Ptosis and strabismus are present in nearly half of patients. Amblyopia has been found in one-third of patients and almost 10% have nystagmus.  Corneal nerves are prominent and a substantial number of individuals have optic nerve abnormalities including drusen, hypoplasia, colobomas and myelinated nerves.  Evidence of an anterior stromal dystrophy, cataracts, or panuveitis is seen in a minority of patients.  About 95% of patients have some ocular abnormalities.

Systemic Features: 

Patients are short in stature.  Birth weight and length may be normal but lymphedema is often present in newborns.  The neck is usually webbed (pterygium colli) and the ears low-set.  The sternum may be deformed.  Cardiac anomalies such as coarctation of the aorta, pulmonary valve stenosis, hypertrophic cardiomyopathy, and septal defects are present in more than half of patients.  Dysplasia of the pulmonic valve has been reported as well.  Thrombocytopenia and abnormal platelet function with abnormalities of coagulation factors are found in about 50% of cases resulting in easy bruising and prolonged bleeding.  Cryptorchidism is common in males.  Some patients have intellectual disabilities with speech and language problems.  Most have normal intelligence.   

Parents of affected children often have subtle signs of Noonan Syndrome.

Genetics

This is an autosomal dominant disorder that can result from mutations in at least 7 genes.  Nearly half are caused by mutations in the PTPN11 gene (12q24.1) (163950).  Mutations in the SOS1 gene (2p22-p21) cause NS4 (610733) and account for 10-20% of cases, those in the RAF1 gene (3p25) causing NS5 (611553) for about the same proportion, and mutations in the KRAS gene (12p12.1) (NS3; 609942) cause about 1%.  Mutations in BRAF (7q34) causing NS7 (613706), NRAS (1p13.2) responsible for NS6 (613224), and MEK1 genes have also been implicated and it is likely that more mutations will be found.  The phenotype is similar in all individuals but with some variation in the frequency and severity of specific features.  New mutations are common. 

Several families suggestive of autosomal recessive inheritance (NS2) (605275) have been reported but no homozygous genotype has been identified.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for most of the developmental problems but some patients benefit from special education. Cardiac surgery may be required in some cases to correct the developmental defects.  Bleeding problems can be treated with supplementation of the defective coagulation factor.  Growth hormone therapy can increase the growth velocity.

References
Article Title: 

Update on turner and noonan syndromes

Chacko E, Graber E, Regelmann MO, Wallach E, Costin G, Rapaport R. Update on turner and noonan syndromes. Endocrinol Metab Clin North Am. 2012 Dec;41(4):713-34. Epub 2012 Sep 28.

PubMed ID: 
23099266

Fabry Disease

Clinical Characteristics
Ocular Features: 

Fabry disease is a lysosomal enzyme (alpha-galactosidase A) deficiency resulting in the accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids throughout the body.  The signature ocular manifestation is the whorl-like corneal pattern of lipid (glycosphingolipid) deposits which are present in both hemizygous males and heterozygous females.  These are sometimes referred to as cornea verticillata or Fleischer vortex dystrophy with a pattern similar to that seen in some patients using atabrine or amiodarone.  A general 'haze' throughout the cornea is even more common.  Lens opacities may also be distinctive and generally are one of two types: spoke-like opacities beneath the posterior capsule among males, and wedge-shaped anterior subcapsular deposits, again primarily in males.  The corneal and lens opacities seldom cause significant vision problems.

Involvement of the ocular vessels is present in almost all patients.  A notable increase in tortuosity of conjunctival vessels is present in 97% of hemizygous males and 78% of heterozygous females.  Increased retinal vessel tortuosity is less common but arteriolar involvement significantly increases the risk of central retinal artery occlusions.  An 11 yo Turkish female heterozygote with a cilioretinal artery occlusion and anterior ischemic optic neuropathy in one eye has been reported.

Systemic Features: 

The relatively common occurrence and the protean nature of Fabry disease has lead to its designation by some as the Great Imposter, replacing syphilis to which this term was previously applied.  Compounding the diagnostic difficulties in some individuals is the absence of the complete classical phenotype due to the presence of DNA variants that may modify the expression of some the clinical features.

Most signs present in the first or second decade of life with generally earlier onset in males.  The presence of proteinuria before the age of 20 years in the absence of other primary kidney disease should always raise the possibility of Fabry disease.  However, the diagnosis is often not made until the third decade in males and the fourth decade in females.  Glycosphingolipid inclusion deposits in endothelial cells are responsible for the systemic signs and symptoms including renal and heart disease which are the most common causes of premature death.  Small vessel involvement resulting in cerebrovascular disease and painful peripheral neuropathy can be debilitating. The risk of ischemic strokes is increased.  Cardiac manifestations include hypertrophic cardiomyopathy (60%), mainly involving the left ventricle, and dysfunction of the mitral and aortic valves (10 to 25%).  Dysfunction of renal glomeruli may progress to renal failure by the third to fifth decade in males.  The angiokeratomas and angiomas (most pronounced in a swimming trunk pattern) are secondary to vascular involvement of cutaneous vessels but are non-specific since they also occur in other lysosomal diseases.  The life expectancy of females is reduced by about 5 years and for males about 16 years compared with the general US population.

Involvment of the autonomic system manifests as intermittent fever, hypohidrosis, and poor temperature control.  Some patients have periodic crises of severe pain in the extremities as well as intermittent epigastric pain. Hearing loss and episodic tinnitus are common complaints.

Genetics

This is an X-linked disorder and generally assumed to be recessive although some have suggested dominance since most heterozygous females have significant manifestations that can be life-threatening.  The mutations in the responsible gene (GLA), located at Xq22, involve a variety of deletions, rearrangements and single base pair changes.  Defects in the GLA gene lead to dysfunction of the enzyme alpha-galactosidase A resulting in lysosomal deposition of glycosphingolipids throughout the body, especially in vascular endothelial cells.   

The milder disease and increase in the range of clinical manifestations among females is likely a reflection of variable patterns of X-inactivation.

Increased tortuosity of retinal arterioles is also seen in fucidosis (230000), Williams syndrome (194050), and in a condition known as retinal arteriolar tortuosity (611773, 180000).

Pedigree: 
X-linked dominant, father affected
X-linked dominant, mother affected
Treatment
Treatment Options: 

Enzyme replacement therapy using agalsidase alfa (commercially available as Febrazyme (tm)) have shown promise as measured by renal function, pain intensity, left ventricular size, and general quality of life.  However, the impact on longevity remains to be determined.  Evidence suggests that early treatment is associated with improved outcomes. The corneal and lenticular opacities generally do not require treatment.

Continuous release of cardiac troponin I (cTNI) with elevated serum levels may be a clue to the severity of heart involvement.

References
Article Title: 

Favourable effect of early versus late start of enzyme replacement therapy on plasma globotriaosylsphingosine levels in men with classical Fabry disease

Arends M, Wijburg FA, Wanner C, Vaz FM, van Kuilenburg ABP, Hughes DA, Biegstraaten M, Mehta A, Hollak CEM, Langeveld M. Favourable effect of early versus late start of enzyme replacement therapy on plasma globotriaosylsphingosine levels in men with classical Fabry disease. Mol Genet Metab. 2017 May 4. pii: S1096-7192(17)30156-7.

PubMed ID: 
28495078

Continuous cardiac troponin I release in fabry disease

Feustel A, Hahn A, Schneider C, Sieweke N, Franzen W, Gunduz D, Rolfs A, Tanislav C. Continuous cardiac troponin I release in fabry disease. PLoS One. 2014 Mar 13;9(3):e91757. doi: 10.1371/journal.pone.0091757. eCollection 2014.

PubMed ID: 
24626231

Fabry disease: overall effects of agalsidase alfa treatment

Beck M, Ricci R, Widmer U, Dehout F, de Lorenzo AG, Kampmann C, Linhart A,
Sunder-Plassmann G, Houge G, Ramaswami U, Gal A, Mehta A. Fabry disease: overall effects of agalsidase alfa treatment. Eur J Clin Invest. 2004 Dec;34(12):838-44.

PubMed ID: 
15606727
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