Ataxia, and Waddling gait

CMTDIG is an autosomal dominant neurologic disorder with a highly variable phenotype. Most affected individuals have onset in the first or second decades of slowly progressive distal motor weakness and atrophy, resulting in gait instability and distal upper limb impairment, as well as distal sensory impairment. More severely affected individuals may have pes cavus and claw hands and become wheelchair-bound, whereas other affected individuals have later onset with a milder disease course. Electrophysiologic studies tend to show median motor nerve conduction velocities (NCV) in the 'intermediate' range, between 25 and 45 m/s (summary by Berciano et al., 2017).In a review of intermediate CMT, Berciano et al. (2017) noted that advanced axonal degeneration may induce secondary demyelinating changes resulting in decreased NCV and attenuated compound muscle action potential (CMAP) in median nerve conduction studies. They thus suggested that testing the upper arm, axilla to elbow, may provide more accurate assessment of NCV and CMAP and reveal an intermediate phenotype (review by Berciano et al., 2017).For a discussion of genetic heterogeneity of CMTDI, see {606482}.

• Generalized hypotonia
• Hearing impairment
• Ataxia
• Nystagmus
• Muscle weakness

SOURCES: OMIM MENDELIAN

Homocystinuria due to methylene tetrahydrofolate reductase (MTHFR) deficiency is a metabolic disorder characterised by neurological manifestations.

HOMOCYSTINURIA DUE TO METHYLENE TETRAHYDROFOLATE REDUCTASE DEFICIENCY Is also known as methylenetetrahydrofolate reductase deficiency|mthfr deficiency|methylene tetrahydrofolate reductase deficiency

• Intellectual disability
• Seizures
• Global developmental delay
• Generalized hypotonia
• Microcephaly

SOURCES: OMIM ORPHANET MENDELIAN

Spastic paraplegia-severe developmental delay-epilepsy syndrome is a rare, genetic, complex spastic paraplegia disorder characterized by an infantile-onset of psychomotor developmental delay with severe intellectual disability and poor speech acquisition, associated with seizures (mostly myoclonic), muscular hypotonia which may be noted at birth, and slowly progressive spasticity in the lower limbs leading to severe gait disturbances. Ocular abnormalities and incontinence are commonly associated. Other symptoms may include verbal dyspraxia, hypogenitalism, macrocephaly and sensorineural hearing loss, as well as dystonic movements and ataxia with upper limb involvement.

SPASTIC PARAPLEGIA-SEVERE DEVELOPMENTAL DELAY-EPILEPSY SYNDROME Is also known as spastic paraplegia-psychomotor retardation-seizures syndrome|spprs syndrome

• Intellectual disability
• Seizures
• Global developmental delay
• Short stature
• Generalized hypotonia

SOURCES: OMIM ORPHANET MENDELIAN

Autosomal recessive spastic paraplegia type 23 (SPG23) is a rare, complex type of hereditary spastic paraplegia that presents in childhood with progressive spastic paraplegia, associated with peripheral neuropathy, skin pigment abnormalities (i.e. vitiligo, hyperpigmentation, diffuse lentigines), premature graying of hair, and characteristic facies (i.e. thin with ''sharp'' features). The SPG23 phenotype has been mapped to a locus on chromosome 1q24-q32.

AUTOSOMAL RECESSIVE SPASTIC PARAPLEGIA TYPE 23 Is also known as spastic paraparesis-vitiligo-premature graying-characteristic facies syndrome|lison syndrome|spg23|spastic paraparesis, vitiligo, premature graying, characteristic facies|spastic paraplegia with pigmentary abnormalities

• Seizures
• Short stature
• Microcephaly
• Ataxia
• Micrognathia

SOURCES: ORPHANET OMIM MESH MENDELIAN

Myasthenia gravis is a disease that causes weakness in the muscles under your control. It happens because of a problem in communication between your nerves and muscles. Myasthenia gravis is an autoimmune disease. Your body's own immune system makes antibodies that block or change some of the nerve signals to your muscles. This makes your muscles weaker. Common symptoms are trouble with eye and eyelid movement, facial expression and swallowing. But it can also affect other muscles. The weakness gets worse with activity, and better with rest. There are medicines to help improve nerve-to-muscle messages and make muscles stronger. With treatment, the muscle weakness often gets much better. Other drugs keep your body from making so many abnormal antibodies. There are also treatments which filter abnormal antibodies from the blood or add healthy antibodies from donated blood. Sometimes surgery to take out the thymus gland helps. For some people, myasthenia gravis can go into remission and they do not need medicines. The remission can be temporary or permanent. If you have myasthenia gravis, it is important to follow your treatment plan. If you do, you can expect your life to be normal or close to it. NIH: National Institute of Neurological Disorders and Stroke

• Intellectual disability
• Seizures
• Ataxia
• Nystagmus
• Sensorineural hearing impairment

SOURCES: ORPHANET MENDELIAN

Autosomal recessive limb-girdle muscular dystrophy type 2S (LGMD2S) is a form of limb-girdle muscular dystrophy characterized by childhood-onset of progressive proximal muscle weakness (leading to reduced ambulation) with myalgia and fatigue, in addition to infantile hyperkinetic movements, truncal ataxia, and intellectual disability. Additional manifestations include scoliosis, hip dysplasia, and less commonly, ocular features (e.g. myopia, cataract) and seizures.

AUTOSOMAL RECESSIVE LIMB-GIRDLE MUSCULAR DYSTROPHY TYPE 2S Is also known as muscular dystrophy, limb-girdle, type 2s|lgmd2s

• Intellectual disability
• Seizures
• Global developmental delay
• Short stature
• Generalized hypotonia

SOURCES: OMIM ORPHANET MENDELIAN

Sialidosis is an autosomal recessive disorder characterized by the progressive lysosomal storage of sialylated glycopeptides and oligosaccharides caused by a deficiency of the enzyme neuraminidase. Common to the sialidoses is the accumulation and/or excretion of sialic acid (N-acetylneuraminic acid) covalently linked ('bound') to a variety of oligosaccharides and/or glycoproteins (summary by Lowden and O'Brien, 1979). The sialidoses are distinct from the sialurias in which there is storage and excretion of 'free' sialic acid, rather than 'bound' sialic acid; neuraminidase activity in sialuria is normal or elevated. Salla disease (OMIM ) is a form of 'free' sialic acid disease. ClassificationLowden and O'Brien (1979) provided a logical nosology of neuraminidase deficiency into sialidosis type I and type II. Type I is the milder form, also known as the 'normosomatic' type or the cherry red spot-myoclonus syndrome. Sialidosis type II is the more severe form with an earlier onset, and is also known as the 'dysmorphic' type. Type II has been subdivided into juvenile and infantile forms. Other terms for sialidosis type II are mucolipidosis I and lipomucopolysaccharidosis.

NEURAMINIDASE DEFICIENCY Is also known as neug deficiency|neuraminidase 1 deficiency|glycoprotein neuraminidase deficiency|neu1 deficiency|mucolipidosis i|neu deficiency|lipomucopolysaccharidosis|sialidase deficiency|ml i|sialidosis, type ii

• Intellectual disability
• Seizures
• Global developmental delay
• Short stature
• Generalized hypotonia

SOURCES: OMIM MENDELIAN

Camurati-Englemann disease (CED) is a rare, clinically variable bone dysplasia syndrome characterized by hyperostosis of the long bones, skull, spine and pelvis, associated with severe pain in the extremities, a wide-based waddling gait, joint contractures, muscle weakness and easy fatigability. Camurati-Englemann disease (CED) is a rare, clinically variable bone dysplasia syndrome characterized by hyperostosis of the long bones, skull, spine and pelvis, associated with severe pain in the extremities, a wide-based waddling gait, joint contractures, muscle weakness and easy fatigability.

CAMURATI-ENGELMANN DISEASE Is also known as diaphyseal dysplasia 1, progressive|engelmann disease|progressive diaphyseal dysplasia|dpd1|ced|pdd

• Hearing impairment
• Scoliosis
• Ataxia
• Muscle weakness
• Abnormal facial shape

SOURCES: OMIM ORPHANET MENDELIAN

Glutaric aciduria II (GA2) is an autosomal recessively inherited disorder of fatty acid, amino acid, and choline metabolism. It differs from GA I (GA1 ) in that multiple acyl-CoA dehydrogenase deficiencies result in large excretion not only of glutaric acid, but also of lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids. GA II results from deficiency of any 1 of 3 molecules: the alpha (ETFA) and beta (ETFB) subunits of electron transfer flavoprotein, and electron transfer flavoprotein dehydrogenase (ETFDH). The clinical picture of GA II due to the different defects appears to be indistinguishable; each defect can lead to a range of mild or severe cases, depending presumably on the location and nature of the intragenic lesion, i.e., mutation, in each case (Goodman, 1993; Olsen et al., 2003).The heterogeneous clinical features of patients with MADD fall into 3 classes: a neonatal-onset form with congenital anomalies (type I), a neonatal-onset form without congenital anomalies (type II), and a late-onset form (type III). The neonatal-onset forms are usually fatal and are characterized by severe nonketotic hypoglycemia, metabolic acidosis, multisystem involvement, and excretion of large amounts of fatty acid- and amino acid-derived metabolites. Symptoms and age at presentation of late-onset MADD are highly variable and characterized by recurrent episodes of lethargy, vomiting, hypoglycemia, metabolic acidosis, and hepatomegaly often preceded by metabolic stress. Muscle involvement in the form of pain, weakness, and lipid storage myopathy also occurs. The organic aciduria in patients with the late-onset form of MADD is often intermittent and only evident during periods of illness or catabolic stress (summary by Frerman and Goodman, 2001).Importantly, riboflavin treatment has been shown to ameliorate the symptoms and metabolic profiles in many MADD patients, particularly those with type III, the late-onset and mildest form (Liang et al., 2009).

MULTIPLE ACYL-COA DEHYDROGENASE DEFICIENCY; MADD Is also known as ema|ethylmalonic-adipicaciduria|glutaric aciduria ii|ga ii|glutaric acidemia ii|ga2

• Intellectual disability
• Seizures
• Global developmental delay
• Generalized hypotonia
• Ataxia

SOURCES: OMIM ORPHANET MENDELIAN

Axonal Charcot-Marie-Tooth disease type 2CC is an autosomal dominant peripheral neuropathy that predominantly affects the lower limbs, resulting in muscle weakness and atrophy and gait impairment. Other features include distal sensory impairment and less severe involvement of the upper limbs. The age at onset and severity are variable (summary by Rebelo et al., 2016).For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT type 2, see CMT2A (OMIM ).

CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2CC; CMT2CC Is also known as charcot-marie-tooth neuropathy, type 2cc

• Muscle weakness
• Peripheral neuropathy
• Gait disturbance
• Myopathy
• Hyporeflexia

SOURCES: OMIM MENDELIAN