Leukodystrophy, demyelinating, adult-onset, autosomal dominant, typical

A slowly progressive and fatal demyelinating leukodystrophy, presenting in the fourth or fifth decade of life. Clinically characterized by early autonomic abnormalities, pyramidal and cerebellar dysfunction, and symmetric demyelination of the CNS. It differs from multiple sclerosis and other demyelinating disorders in that neuropathology shows preservation of oligodendroglia in the presence of subtotal demyelination and lack of astrogliosis.

Fumarase deficiency

A severe autosomal recessive metabolic disorder characterized by early-onset hypotonia, profound psychomotor retardation, and brain abnormalities, such as agenesis of the corpus callosum, gyral defects, and ventriculomegaly. Many patients show neonatal distress, metabolic acidosis, and/or encephalopathy.

Ehlers-Danlos syndrome, kyphoscoliotic type, 2

A form of Ehlers-Danlos syndrome, a group of connective tissue disorders characterized by skin hyperextensibility, articular hypermobility, and tissue fragility. EDSKSCL2 is an autosomal recessive form characterized by severe generalized hypotonia at birth, myopathy, early-onset progressive kyphoscoliosis, joint hypermobility without contractures, hyperelastic skin with follicular hyperkeratosis, easy bruising, and occasional abnormal scarring, sensorineural hearing impairment, and normal pyridinoline excretion in urine.

Pontocerebellar hypoplasia 1A

A form of pontocerebellar hypoplasia, a disorder characterized by structural defects of the pons and cerebellum, evident upon brain imaging. PCH1A is an autosomal recessive form characterized by an abnormally small cerebellum and brainstem, central and peripheral motor dysfunction from birth, gliosis and spinal cord anterior horn cells degeneration resembling infantile spinal muscular atrophy. Additional features include muscle hypotonia, congenital contractures and respiratory insufficiency that is evident at birth.

Mucopolysaccharidosis 3A

A severe form of mucopolysaccharidosis type 3, an autosomal recessive lysosomal storage disease due to impaired degradation of heparan sulfate. MPS3 is characterized by severe central nervous system degeneration, but only mild somatic disease. Onset of clinical features usually occurs between 2 and 6 years; severe neurologic degeneration occurs in most patients between 6 and 10 years of age, and death occurs typically during the second or third decade of life. MPS3A is characterized by earlier onset, rapid progression of symptoms and shorter survival.

Holoprosencephaly 10

A form of holoprosencephaly, a structural anomaly of the brain in which the developing forebrain fails to correctly separate into right and left hemispheres. It is a genetically and clinically heterogeneous disorder with a wide spectrum of severity, ranging from alobar holoprosencephaly with severe facial abnormalities, such as cyclopia and proboscis, to mild forms that include lobar or microform holoprosencephaly, without cerebral malformations and with mild craniofacial defects. HPE10 inheritance pattern is autosomal recessive. Autosomal dominant inheritance with incomplete penetrance or oligogenic inheritance have been reported in some families.

Leber hereditary optic neuropathy

A maternally inherited form of Leber hereditary optic neuropathy, a mitochondrial disease resulting in bilateral painless loss of central vision due to selective degeneration of the retinal ganglion cells and their axons. The disorder shows incomplete penetrance and male predominance. Cardiac conduction defects and neurological defects have also been described in some LHON patients. LHON results from primary mitochondrial DNA mutations affecting the respiratory chain complexes.

MACS syndrome

A complex disorder of elastic tissue characterized by sagging skin and occasionally by life-threatening visceral complications.

Pontocerebellar hypoplasia 1B

A severe autosomal recessive neurologic disorder characterized by a combination of cerebellar and spinal motor neuron degeneration beginning at birth. There is diffuse muscle weakness, progressive microcephaly, global developmental delay, and brainstem involvement.

Mitochondrial complex II deficiency, nuclear type 1

A disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations. Clinical features include psychomotor regression in infants, poor growth with lack of speech development, severe spastic quadriplegia, dystonia, progressive leukoencephalopathy, muscle weakness, exercise intolerance, cardiomyopathy. Some patients manifest Leigh syndrome or Kearns-Sayre syndrome. MC2DN1 inheritance is autosomal recessive.

Van der Woude syndrome 1

An autosomal dominant developmental disorder characterized by lower lip pits, cleft lip and/or cleft palate.

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 1

A disorder characterized by progressive weakness of ocular muscles and levator muscle of the upper eyelid. In a minority of cases, it is associated with skeletal myopathy, which predominantly involves axial or proximal muscles and which causes abnormal fatigability and even permanent muscle weakness. Ragged-red fibers and atrophy are found on muscle biopsy. A large proportion of chronic ophthalmoplegias are associated with other symptoms, leading to a multisystemic pattern of this disease. Additional symptoms are variable, and may include cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism.

Hennekam lymphangiectasia-lymphedema syndrome 3

A form of Hennekam lymphangiectasia-lymphedema syndrome, a generalized lymph-vessels dysplasia characterized by intestinal lymphangiectasia with severe lymphedema of the limbs, genitalia and face. In addition, affected individuals have unusual facies and some manifest intellectual disability. HKLLS3 is characterized by widespread congenital edema, facial dysmorphism and protein-losing enteropathy of variable severity. HKLLS3 transmission pattern is consistent with autosomal recessive inheritance.

Pontocerebellar hypoplasia 10

A form of pontocerebellar hypoplasia, a disorder characterized by structural defects of the pons and cerebellum, evident upon brain imaging. PCH10 features include cortical dysgenesis marked by a simplified gyral pattern, cortical atrophy, mild or focal cerebellar vermian volume loss, delayed myelination, progressive microcephaly, global growth and developmental delays, severe intellectual disabilities, and seizures refractory to treatment.

Mitochondrial complex I deficiency, nuclear type 17

A form of mitochondrial complex I deficiency, the most common biochemical signature of mitochondrial disorders, a group of highly heterogeneous conditions characterized by defective oxidative phosphorylation, which collectively affects 1 in 5-10000 live births. Clinical disorders have variable severity, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. MC1DN17 transmission pattern is consistent with autosomal recessive inheritance.

Dystonia 3, torsion, X-linked

An X-linked dystonia-parkinsonism disorder. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. DYT3 is characterized by severe progressive torsion dystonia followed by parkinsonism. It has a well-defined pathology of extensive neuronal loss and mosaic gliosis in the striatum (caudate nucleus and putamen) which appears to resemble that in Huntington disease.

Neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties

An autosomal dominant disorder characterized by severe neonatal hypotonia, respiratory and feeding difficulties, encephalopathy, and severe developmental delay. Additional common features may include seizures, exaggerated startle reflex, abnormal movements, and dysmorphic facial features.

Mucopolysaccharidosis-plus syndrome

A form of mucopolysaccharidosis, a group of lysosomal storage diseases characterized by defective degradation of glycosaminoglycans, resulting in their excessive accumulation and secretion. The diseases are progressive and often display a wide spectrum of clinical severity. MPSPS is an autosomal recessive form characterized by coarse facial features, dysostosis multiplex, hepatosplenomegaly, respiratory difficulties, intellectual disability, developmental delay, pyramidal signs, severe chronic anemia, renal involvement and cardiac defects. Laboratory analyses show proteinuria with glomerular foamy cells, excess secretion of urinary glycosaminoglycans, and extremely high levels of plasma heparan sulphate. Disease onset is in infancy. Most patients die in the first years of life due to cardiorespiratory failure.

Noonan syndrome 9

A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells.

Pontocerebellar hypoplasia 6

A disorder characterized by an abnormally small cerebellum and brainstem, infantile encephalopathy, generalized hypotonia, lethargy and poor feeding. Recurrent apnea, intractable seizures occur early in the course of this condition.

Peroxisome biogenesis disorder complementation group 3

A peroxisomal disorder arising from a failure of protein import into the peroxisomal membrane or matrix. The peroxisome biogenesis disorders (PBD group) are genetically heterogeneous with at least 14 distinct genetic groups as concluded from complementation studies. Include disorders are: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinct from RCDP and constitute a clinical continuum of overlapping phenotypes known as the Zellweger spectrum (PBD-ZSS).

Caffey disease

An autosomal dominant disorder characterized by an infantile episode of massive subperiosteal new bone formation that typically involves the diaphyses of the long bones, mandible, and clavicles. The involved bones may also appear inflamed, with painful swelling and systemic fever often accompanying the illness. The bone changes usually begin before 5 months of age and resolve before 2 years of age.

Pontocerebellar hypoplasia 1C

A severe autosomal recessive neurodegenerative disease characterized by cerebellar and corpus callosum hypoplasia, abnormal myelination of the central nervous system, and spinal motor neuron disease. Affected individuals manifest failure to thrive, severe muscle weakness, spasticity and psychomotor retardation. Vision and hearing are impaired.

Congenital heart defects, multiple types, 9

An autosomal recessive disorder characterized by congenital developmental abnormalities involving structures of the heart. CHTD9 features include common arterial trunk, tetralogy of Fallot, interrupted aortic arch, right aortic arch, ventricular hypoplasia, and hypoplastic left heart, as well as other vascular and valvular anomalies.

Grange syndrome

An autosomal recessive syndrome of stenosis or occlusion of multiple arteries, including renal, abdominal, cerebral and probably coronary arteries, congenital heart defects, brachydactyly, syndactyly, bone fragility, and learning disabilities.

Neuropathy, ataxia, and retinitis pigmentosa

A syndrome characterized by variable combination of developmental delay, psychomotor retardation, hearing loss, optic atrophy and retinitis pigmentosa, dementia, seizures, ataxia, proximal neurogenic muscle weakness, and sensory neuropathy.

Combined oxidative phosphorylation deficiency 9

A mitochondrial disease characterized by failure to thrive, poor feeding, hypertrophic cardiomyopathy, hepatomegaly, and psychomotor retardation. Death in infancy has been observed in some cases.

Perrault syndrome 6

A form of Perrault syndrome, a sex-influenced disorder characterized by sensorineural deafness in both males and females, and ovarian dysgenesis in females. Affected females have primary amenorrhea, streak gonads, and infertility, whereas affected males show normal pubertal development and are fertile. PRLTS6 inheritance is autosomal recessive.

Intellectual developmental disorder, autosomal dominant 26

A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Additional MRD26 features include autism, short stature, microcephaly, cerebral palsy, and facial dysmorphisms.

Spastic paraplegia 8, autosomal dominant

A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body.

Den Hoed-de Boer-Voisin syndrome

A disorder characterized by global developmental delay, moderately to severely impaired intellectual development, poor or absent speech, delayed motor skills, and early-onset epilepsy in many patients. Most affected individuals have feeding difficulties, poor overall growth, dysmorphic facial features, and significant dental anomalies resembling amelogenesis imperfecta. More variable features include visual defects, behavioral abnormalities, and non-specific involvement of other organ systems. DHDBV transmission pattern is consistent with autosomal dominant inheritance with incomplete penetrance and variable expressivity.

Facial clefting, oblique, 1

A rare form of facial clefting. A facial cleft is any of the fissures between the embryonic prominences that normally unite to form the face.

Combined oxidative phosphorylation deficiency 40

An autosomal recessive mitochondrial disorder characterized by prenatal or infantile onset, fetal hydrops, severe hypertrophic cardiomyopathy, poor growth, sensorineural hearing loss, hepatic dysfunction, lactic acidosis, and decreased activities of mitochondrial respiratory complexes I, III, IV, and V. The disorder is lethal, with death occurring in infancy.

Mucopolysaccharidosis 7

A form of mucopolysaccharidosis, a group of lysosomal storage diseases characterized by defective degradation of glycosaminoglycans, resulting in their excessive accumulation and secretion. The diseases are progressive and often display a wide spectrum of clinical severity. MPS7 is an autosomal recessive form with a highly variable phenotype, ranging from severe lethal hydrops fetalis to mild forms with survival into adulthood. Most patients with the intermediate phenotype show hepatomegaly, skeletal anomalies, coarse facies, and variable degrees of mental impairment.

Deafness, autosomal dominant, 78

A form of non-syndromic deafness characterized by congenital, profound bilateral sensorineural hearing loss affecting all frequencies. Some patients may have mild motor delay early in life due to vestibular dysfunction. Sensorineural hearing loss results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information.

Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism

An autosomal recessive neurodegenerative disorder characterized by early childhood onset of cerebellar ataxia and mild intellectual disabilities associated with diffuse hypomyelination apparent on brain MRI. Variable features include oligodontia and/or hypogonadotropic hypogonadism.

Mitochondrial complex I deficiency, nuclear type 37

A form of mitochondrial complex I deficiency, the most common biochemical signature of mitochondrial disorders, a group of highly heterogeneous conditions characterized by defective oxidative phosphorylation, which collectively affects 1 in 5-10000 live births. Clinical disorders have variable severity, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. MC1DN37 features include developmental delay, cerebral atrophy, epilepsy, growth retardation, congenital myopathy with disproportion of fibers, and severely decreased activity of complex I. MC1DN37 transmission pattern is consistent with autosomal recessive inheritance.

Mevalonic aciduria

Accumulation of mevalonic acid which causes a variety of symptoms such as psychomotor retardation, dysmorphic features, cataracts, hepatosplenomegaly, lymphadenopathy, anemia, hypotonia, myopathy, and ataxia.

Pontocerebellar hypoplasia 8

An autosomal recessive neurodevelopmental disorder characterized by severe psychomotor retardation, abnormal movements, hypotonia, spasticity, and variable visual defects. Brain MRI shows pontocerebellar hypoplasia, decreased cerebral white matter, and a thin corpus callosum.

Ehlers-Danlos syndrome, arthrochalasia type, 2

A form of Ehlers-Danlos syndrome, a connective tissue disorder characterized by hyperextensible skin, atrophic cutaneous scars due to tissue fragility and joint hyperlaxity. EDSARTH2 is an autosomal dominant condition characterized by frequent congenital hip dislocation and extreme joint laxity with recurrent joint subluxations and minimal skin involvement.

Multiple sulfatase deficiency

A clinically and biochemically heterogeneous disorder caused by the simultaneous impairment of all sulfatases, due to defective post-translational modification and activation. It combines features of individual sulfatase deficiencies such as metachromatic leukodystrophy, mucopolysaccharidosis, chondrodysplasia punctata, hydrocephalus, ichthyosis, neurologic deterioration and developmental delay.

Mucopolysaccharidosis 2

An X-linked lysosomal storage disease characterized by intracellular accumulation of heparan sulfate and dermatan sulfate and their excretion in urine. Most children with MPS2 have a severe form with early somatic abnormalities including skeletal deformities, hepatosplenomegaly, and progressive cardiopulmonary deterioration. A prominent feature is neurological damage that presents as developmental delay and hyperactivity but progresses to intellectual disability and dementia. They die before 15 years of age, usually as a result of obstructive airway disease or cardiac failure. In contrast, those with a mild form of MPS2 may survive into adulthood, with attenuated somatic complications and often without intellectual disability.

Donnai-Barrow syndrome

An autosomal recessive syndrome characterized by complete or partial agenesis of the corpus callosum, congenital diaphragmatic hernia, facial dysmorphology, ocular anomalies, sensorineural hearing loss, developmental delay, and proteinuria. There is variability in the expression of some features, such as diaphragmatic hernia, corpus callosum anomalies and proteinuria.

Intellectual developmental disorder, autosomal dominant 21

A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Additional MRD21 features include short stature, microcephaly, and developmental delay.

Multiple congenital anomalies-hypotonia-seizures syndrome 3

An autosomal recessive syndrome characterized by distinct facial features, intellectual disability, hypotonia and seizures, in combination with abnormal skeletal, endocrine, and ophthalmologic findings including impaired vision, as well as abnormal motility of the eyes.

Mitochondrial DNA depletion syndrome 17

An autosomal recessive mitochondrial disorder characterized by childhood onset of rapidly progressive encephalopathy, stroke-like episodes, lactic acidosis, hypocitrullinemia, multiple defects of oxidative phosphorylation, mitochondrial complex I and IV deficiency, and reduced mtDNA copy number.

Pontocerebellar hypoplasia 1D

An autosomal recessive neurologic disorder with onset at birth or in infancy, and characterized by progressive axonal motor neuronopathy, severe generalized hypotonia, respiratory insufficiency, and cerebellar atrophy. Death in childhood may occur.

Peroxisome biogenesis disorder complementation group 1

A peroxisomal disorder arising from a failure of protein import into the peroxisomal membrane or matrix. The peroxisome biogenesis disorders (PBD group) are genetically heterogeneous with at least 14 distinct genetic groups as concluded from complementation studies. Include disorders are: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinct from RCDP and constitute a clinical continuum of overlapping phenotypes known as the Zellweger spectrum (PBD-ZSS).

Mitochondrial complex IV deficiency, nuclear type 3

An autosomal recessive mitochondrial disorder characterized by cytochrome c oxidase deficiency. Clinical features include muscle weakness, hypotonia, ataxia, ptosis, metabolic acidosis, poor feeding, delayed motor development, anemia, sensorineural hearing loss, and cardiomyopathy.

Mitochondrial complex IV deficiency, nuclear type 1

An autosomal recessive disorder of the mitochondrial respiratory chain characterized by early-onset, rapidly progressive encephalopathy, neurodegeneration, and loss of motor and cognitive skills. Affected individuals show hypotonia, failure to thrive, loss of the ability to sit or walk, poor communication, poor eye contact, oculomotor abnormalities, as well as deafness, ataxia, tremor, and brisk tendon reflexes. Brain imaging shows bilateral symmetric lesions in the basal ganglia. Lactate levels in serum and cerebrospinal fluid are increased. Patient tissues show decreased levels and activity of mitochondrial respiratory complex IV. Death in childhood may occur, often due to central respiratory failure.

Medulloblastoma

Malignant, invasive embryonal tumor of the cerebellum with a preferential manifestation in children.

Peroxisome biogenesis disorder complementation group 9

A peroxisomal disorder arising from a failure of protein import into the peroxisomal membrane or matrix. The peroxisome biogenesis disorders (PBD group) are genetically heterogeneous with at least 14 distinct genetic groups as concluded from complementation studies. Include disorders are: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinct from RCDP and constitute a clinical continuum of overlapping phenotypes known as the Zellweger spectrum (PBD-ZSS).

Joubert syndrome 15

An autosomal recessive disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy, renal disease, liver fibrosis and polydactyly.

Meier-Gorlin syndrome 4

A syndrome characterized by bilateral microtia, aplasia/hypoplasia of the patellae, and severe intrauterine and postnatal growth retardation with short stature and poor weight gain. Additional clinical findings include anomalies of cranial sutures, microcephaly, apparently low-set and simple ears, microstomia, full lips, highly arched or cleft palate, micrognathia, genitourinary tract anomalies, and various skeletal anomalies. While almost all cases have primordial dwarfism with substantial prenatal and postnatal growth retardation, not all cases have microcephaly, and microtia and absent/hypoplastic patella are absent in some. Despite the presence of microcephaly, intellect is usually normal.

Pelger-Huet anomaly

An autosomal dominant inherited abnormality of granulocytes, characterized by abnormal ovoid shape, reduced nuclear segmentation and an apparently looser chromatin structure.

Spinocerebellar ataxia 28

Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA28 is an autosomal dominant cerebellar ataxia (ADCA) with a slow progressive course and no evidence of sensory involvement or cognitive impairment.

Mandibuloacral dysplasia progeroid syndrome

A form of mandibuloacral dysplasia, a rare progeroid disorder with clinical and genetic heterogeneity, characterized by growth retardation, craniofacial dysmorphic features due to distal bone resorption, musculoskeletal and skin abnormalities associated with lipodystrophy. MDPS is an autosomal recessive disorder. Clinical features include poor growth, osteoporosis, osteopenia, acroosteolysis of distal phalanges, arterial calcification, renal glomerulosclerosis and severe hypertension.

Pontocerebellar hypoplasia 4

A disorder characterized by an abnormally small cerebellum and brainstem, severe neonatal encephalopathy, microcephaly, myoclonus and muscular hypertonia. There is a severe inferior olivary and pontine neuronal loss and a diffuse white matter gliosis.

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 4

A disorder characterized by progressive weakness of ocular muscles and levator muscle of the upper eyelid. In a minority of cases, it is associated with skeletal myopathy, which predominantly involves axial or proximal muscles and which causes abnormal fatigability and even permanent muscle weakness. Ragged-red fibers and atrophy are found on muscle biopsy. A large proportion of chronic ophthalmoplegias are associated with other symptoms, leading to a multisystemic pattern of this disease. Additional symptoms are variable, and may include cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism.

Poretti-Boltshauser syndrome

An autosomal recessive disorder characterized by cerebellar dysplasia, cerebellar vermis atrophy, cerebellar cysts in most patients, high myopia, variable retinal dystrophy, and eye movement abnormalities including strabismus, ocular apraxia, nystagmus. Affected individuals have ataxia, delayed motor development, language impairment, and intellectual disability with variable severity.

Mitochondrial complex IV deficiency, nuclear type 7

An autosomal recessive mitochondrial disorder characterized by encephalomyopathy resulting in variable clinical manifestations. Features include muscle weakness, gait disturbances, neurodegeneration, cognitive decline, metabolic acidosis, feeding difficulties, poor overall growth, cortical visual impairment, and hypertrophic cardiomyopathy. Serum lactate levels are increased. Patient tissues show decreased levels and activity of mitochondrial respiratory complex IV.

Mucopolysaccharidosis 3C

A form of mucopolysaccharidosis type 3, an autosomal recessive lysosomal storage disease due to impaired degradation of heparan sulfate. MPS3 is characterized by severe central nervous system degeneration, but only mild somatic disease. Onset of clinical features usually occurs between 2 and 6 years; severe neurologic degeneration occurs in most patients between 6 and 10 years of age, and death occurs typically during the second or third decade of life.

Leber hereditary optic neuropathy

A maternally inherited form of Leber hereditary optic neuropathy, a mitochondrial disease resulting in bilateral painless loss of central vision due to selective degeneration of the retinal ganglion cells and their axons. The disorder shows incomplete penetrance and male predominance. Cardiac conduction defects and neurological defects have also been described in some LHON patients. LHON results from primary mitochondrial DNA mutations affecting the respiratory chain complexes.

Ritscher-Schinzel syndrome 3

A form of Ritscher-Schinzel syndrome, a developmental malformation syndrome characterized by cerebellar brain malformations, congenital heart defects, and craniofacial abnormalities. RTSC3 is an autosomal recessive form. Affected individuals show cranio-cerebello-cardiac anomalies, coloboma, microphthalmia, chondrodysplasia punctata, complicated skeletal malformations, periventricular nodular heterotopia and proteinuria.

Autism 15

A complex multifactorial, pervasive developmental disorder characterized by impairments in reciprocal social interaction and communication, restricted and stereotyped patterns of interests and activities, and the presence of developmental abnormalities by 3 years of age. Most individuals with autism also manifest moderate intellectual disability.

Congenital disorder of glycosylation 2D

A multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions.

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 2

A disorder characterized by progressive weakness of ocular muscles and levator muscle of the upper eyelid. In a minority of cases, it is associated with skeletal myopathy, which predominantly involves axial or proximal muscles and which causes abnormal fatigability and even permanent muscle weakness. Ragged-red fibers and atrophy are found on muscle biopsy. A large proportion of chronic ophthalmoplegias are associated with other symptoms, leading to a multisystemic pattern of this disease. Additional symptoms are variable, and may include cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism.

Intellectual developmental disorder, X-linked, syndromic, Billuart type

A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRXSBL patients manifest intellectual disability associated with cerebellar hypoplasia and distinctive facial dysmorphism.

Stickler syndrome 2

An autosomal dominant form of Stickler syndrome, an inherited disorder that associates ocular signs with more or less complete forms of Pierre Robin sequence, bone disorders and sensorineural deafness. Ocular disorders may include juvenile cataract, myopia, strabismus, vitreoretinal or chorioretinal degeneration, retinal detachment, and chronic uveitis. Pierre Robin sequence includes an opening in the roof of the mouth (a cleft palate), a large tongue (macroglossia), and a small lower jaw (micrognathia). Bones are affected by slight platyspondylisis and large, often defective epiphyses. Juvenile joint laxity is followed by early signs of arthrosis. The degree of hearing loss varies among affected individuals and may become more severe over time. Syndrome expressivity is variable.

Mitochondrial complex I deficiency, nuclear type 6

A form of mitochondrial complex I deficiency, the most common biochemical signature of mitochondrial disorders, a group of highly heterogeneous conditions characterized by defective oxidative phosphorylation, which collectively affects 1 in 5-10000 live births. Clinical disorders have variable severity, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. MC1DN6 transmission pattern is consistent with autosomal recessive inheritance.

Arthrogryposis, distal, 2A

A form of distal arthrogryposis, a disease characterized by congenital joint contractures that mainly involve two or more distal parts of the limbs, in the absence of a primary neurological or muscle disease. DA2A is characterized by contractures of the hands and feet, oropharyngeal abnormalities, scoliosis, and a distinctive face that includes a very small oral orifice, puckered lips, and a H-shaped dimple of the chin.

Mitochondrial DNA depletion syndrome 3

A disorder due to mitochondrial dysfunction characterized by onset in infancy of progressive liver failure, hypoglycemia, increased lactate in body fluids, and neurologic abnormalities including hypotonia, encephalopathy, peripheral neuropathy. Affected tissues show both decreased activity of the mtDNA-encoded respiratory chain complexes and mtDNA depletion.

Houge-Janssens syndrome 1

An autosomal dominant disorder characterized by global developmental delay, hypotonia, variably impaired intellectual development, poor speech, and dysmorphic facial features. Additional more variable features may include macrocephaly and seizures.

Pancreatic cancer

A malignant neoplasm of the pancreas. Tumors can arise from both the exocrine and endocrine portions of the pancreas, but 95% of them develop from the exocrine portion, including the ductal epithelium, acinar cells, connective tissue, and lymphatic tissue.

Hypophosphatasia

A metabolic bone disease characterized by defective skeletal mineralization and biochemically by deficient activity of the tissue non-specific isoenzyme of alkaline phosphatase. Four forms are distinguished, depending on the age of onset: perinatal, infantile, childhood and adult type. The perinatal form is the most severe and is almost always fatal. The adult form is mild and characterized by recurrent fractures, osteomalacia, rickets, and loss of teeth. Some cases are asymptomatic, while some patients manifest dental features without skeletal manifestations (odontohypophosphatasia).