Approximately 5% of NMTC is hereditary, occurring as a minor component of a familial cancer syndrome (e.g., familial adenomatous polyposis 175100, Carney complex 160980) or as a primary feature (familial NMTC or FNMTC).
Subsequently, the disease progresses to severe spastic tetraparesis and a pseudobulbar syndrome may be observed. Cognitive function is generally preserved.
Infantile-onset ascending hereditary spastic paralysis is one of a group of genetic disorders known as hereditary spastic paraplegias. These disorders are characterized by progressive muscle stiffness (spasticity) and eventual paralysis of the lower limbs (paraplegia). The spasticity and paraplegia result from degeneration (atrophy) of motor neurons, which are specialized nerve cells in the brain and spinal cord that control muscle movement. Hereditary spastic paraplegias are divided into two types: pure and complicated. The pure types involve only the lower limbs, while the complicated types involve additional areas of the nervous system, affecting the upper limbs and other areas of the body.
Infantile-onset ascending hereditary spastic paralysis (IAHSP) is a neurological disorder characterized by progressive (worsening) weakness and stiffness of muscles in the arms, legs, and face. Initial symptoms usually occur within the first 2 years of life and include weakness of the legs, leg muscles that are abnormally tight and stiff, and eventual paralysis of the legs. Over time, muscle weakness and stiffness travels up (ascends) the body from the legs to the head. IAHSP is caused by mutations in the ALS2 gene and is inherited in an autosomal recessive pattern. Although there is no specific treatment or cure, there may be ways to manage the symptoms, including physical and occupational therapy.
A number sign (#) is used with this entry because a subset of infantile-onset ascending hereditary spastic paralysis (IAHSP) is caused by homozygous mutation in the alsin gene (ALS2; 606352) on chromosome 2q33. Mutations in the same gene cause juvenile amyotrophic lateral sclerosis (205100) or juvenile primary lateral sclerosis (606353). Description Infantile-onset ascending spastic paralysis is an autosomal recessive neurodegenerative disorder characterized by onset in the first years of life of progressive upper and lower motor neuron degeneration resulting in loss of ability to walk in childhood. It initially affects the lower limbs and then ascends to the upper limbs and bulbar muscles, causing dysarthria and dysphagia. Cognition is unaffected (summary by Wakil et al., 2014). Clinical Features Eymard-Pierre et al. (2002) studied 15 patients from 10 families who presented with severe spastic paralysis with an infantile onset and an ascending progression.
Description Schwannomatosis is an adult-onset tumor predisposition syndrome characterized by the development of multiple schwannomas in various areas of the body (summary by Piotrowski et al., 2014).
Multiple schwannomas in the same individual suggest an underlying tumor predisposition syndrome. The most common such syndrome is neurofibromatosis II.
Clinical Features Riccardi and Eichner (1986) designated the classic von Recklinghausen disease (162200) as neurofibromatosis I (NF1) and familial acoustic neuromas (101000) as neurofibromatosis II (NF2). They suggested the existence of an entity they labeled NF III that combines features of both with some additional distinctive features. Cafe-au-lait spots (CLS), freckling, and cutaneous neurofibromas occur as in NF I, although typically the CLS are few in number and pale and may be relatively large, and cutaneous neurofibromas are few in number. The palm of the hands is a characteristic site for cutaneous neurofibromas in NF III. Iris Lisch nodules do not occur. Bilateral acoustic neuromas, posterior fossa and upper cervical meningiomas, and spinal/paraspinal neurofibromas are the predominant features of NF III, but optic gliomas have not been seen.
Frontal 'cowlicks' are usual in the FG syndrome (Thompson et al., 1985). Sharma (1987) found a possible association between twinning and double occipital hair whorls; such was found in 25 of 244 twins, but in only 4 of 166 singletons.
They concluded that sporadic preauricular pits should be regarded as minor malformations of great significance in discovering hidden disorders and in syndrome identification. Mapping In a 3-generation Chinese family comprising 18 members, 7 of whom had preauricular fistulae, Zou et al. (2003) found linkage of the trait to a locus on 8q11.1-q13.3 (2-point lod score = 2.40 at theta = 0.0).
Differential diagnosis The differential diagnosis should include other early-onset progressive neurologic diseases, including infantile Krabbe disease, early-stage Rett syndrome and gangliosidosis (see these terms).
Infantile neuronal ceroid lipofuscinosis Other names Santavuori disease, Hagberg-Santavuori disease, Santavuori-Haltia disease, Infantile Finnish type neuronal ceroid lipofuscinosis, Balkan disease Specialty Endocrinology Infantile neuronal ceroid lipofuscinoses ( INCL ) or Santavuori disease [1] or Hagberg-Santavuori disease [2] or Santavuori-Haltia disease [2] or Infantile Finnish type neuronal ceroid lipofuscinosis [3] or Balkan disease [3] is a form of NCL and inherited as a recessive autosomal genetic trait. The disorder is progressive, degenerative and fatal, extremely rare worldwide – with approximately 60 official cases reported by 1982, [4] perhaps 100 sufferers in total today [ citation needed ] – but relatively common in Finland due to the local founder effect . Contents 1 Presentation 2 Causes 3 Diagnosis 4 Treatment 5 See also 6 References 7 External links Presentation [ edit ] The development of children born with INCL is normal for the first 8–18 months, but will then flounder and start to regress both physically and mentally. Motor skills and speech are lost, and optic atrophy causes blindness . A variety of neurological symptoms, such as epilepsy and myoclonic seizures , appear.
CLN1 disease is an inherited disorder that primarily affects the nervous system. Individuals with this condition have normal development in infancy, but typically by 18 months they become increasingly irritable and begin to lose previously acquired skills (developmental regression). In affected children, nerve cells in the brain die over time, leading to an overall loss of brain tissue (brain atrophy) and an unusually small head (microcephaly ). Children with CLN1 disease have decreased muscle tone (hypotonia), intellectual and motor disability, and rarely are able to speak or walk. Some affected children develop repetitive hand movements. By age 2, individuals with this condition often have muscle twitches (myoclonus), recurrent seizures (epilepsy), and vision loss.
Oppenheimer and Andrews (1959) reported 2 cases: a 4-year-old white male from West Virginia who died from liver failure and had ceroid deposits of liver, spleen and intestinal mucosa, and a white 22-month-old female who at autopsy had ceroid limited largely to hepatic macrophages. The sister and 2 brothers reported by Nelson et al. (1961) may have had the same condition. The isolated case reported by Jonas (1966) may have had the same or a related condition. Menkes (1982) reviewed the paper by Ryan et al. (1970) and suggested, mainly on clinical grounds because the electron microscopy was unsatisfactory, that the correct diagnosis was the Finnish or Santavuori type of infantile neuronal ceroid lipofuscinosis (256730). Inheritance - ? Autosomal recessive Liver - Macrophage ceroid deposits - Liver failure GI - Mucosal ceroid deposits Spleen - Ceroid deposits ▲ Close
Other differential diagnoses include campomelic dysplasia, chondrodysplasia and Stuve Wiedemann syndrome. Antenatal diagnosis Suspicious ultrasound findings include short and/or bowed limbs, skeletal hypomineralization, osteochondral spurs and, sometimes, the absence of certain bones (skull, ribs, vertebrae, pubis).
Rupprecht and Doerfel (1966) described sibs with an unusual syndrome characterized by micromelia with normal stature at birth, sometimes microcephaly, and severe epiphyseal and metaphyseal disturbances in the long bones, vertebrae and ribs.
GP Ib, the von Willebrand factor receptor, is deficient in the Bernard-Soulier syndrome (BSS; 231200), and GP IIb (607759)-IIIa (173470) is deficient in Glanzmann thrombasthenia (273800).
Bleeding diathesis due to a collagen receptor defect is a rare, genetic coagulation disorder characterized by a mild to moderate bleeding tendency due to impaired platelet activation and aggregation in response to collagen, or impaired platelet-vessel wall interaction, resulting from a collagen receptor defect. Patients manifest with ecchymoses, epistaxis, menorrhagia, and/or post-traumatic and post-surgery bleeding complications. Laboratory analysis reveals prolonged bleeding time and, occasionally, mild thrombocytopenia.
MED23 is a gene that plays a role in brain development. Mutations in MED23 cause difficulty swallowing, screaming spells, reflux, and gastrointestinal problems in infants. Children with MED23 gene mutations have profound learning and developmental delays impairing muscle control, mobility, communication, and speech. MED23 gene mutations do not cause changes in growth or physical appearance. MED23 is inherited in an autosomal recessive fashion.
Molecular Genetics In 31 multiplex consanguineous families that appeared to have novel dysmorphology syndromes, including the Saudi family originally described by Alkuraya (2011), Shaheen et al. (2016) performed autozygome analysis followed by whole-exome and whole-genome sequencing.
Onset during childhood or adulthood is characterised by mainly proximal muscle weakness, a rigid spine syndrome and a slowly progressive disease course.
A number sign (#) is used with this entry because severe X-linked reducing body myopathy-1 with infantile or early childhood onset (RBMX1A) is caused by mutation in the FHL1 gene (300163) on chromosome Xq26. Description Reducing-body myopathy (RBM) is a rare myopathy characterized pathologically by the presence of intracytoplasmic inclusion bodies strongly stained by menadione-linked alpha-glycerophosphate dehydrogenase (MAG) in the absence of substrate, alpha-glycerophosphate. The term 'reducing body' refers to the reducing activity of the inclusions to nitroblue tetrazolium (NBT) in the absence of substrate. This condition is also commonly associated with rimmed vacuoles and cytoplasmic bodies. The clinical features of RBM are variable; a severe form has onset in infancy or early childhood and results in severe disability or early death, and a less severe form has onset in late childhood or adulthood (RBMX1B; 300718) (summary by Liewluck et al., 2007 and Shalaby et al., 2009).
Infants may also develop a ''sepsis-like syndrome'' characterized by hypotension, leucopenia or leukocytosis, neutropenia, thrombocytopenia, and disseminated intravascular coagulopathy.
Differential diagnosis Differential diagnosis includes the other hereditary sensory and autonomic neuropathies (HSAN), especially HSAN II, as well as diabetic foot syndrome, alcoholic neuropathy, neuropathies caused by other neurotoxins/drugs, immune mediated neuropathy, amyloidosis, spinal cord diseases, tabes dorsalis, lepra neuropathy, or decaying skin tumours like amelanotic melanoma (see these terms).
Summary Clinical characteristics. SPTLC1 -related hereditary sensory neuropathy (HSN) is an axonal form of hereditary motor and sensory neuropathy distinguished by prominent early sensory loss and later positive sensory phenomena including dysesthesia and characteristic "lightning" or "shooting" pains. Loss of sensation can lead to painless injuries, which, if unrecognized, result in slow wound healing and subsequent osteomyelitis requiring distal amputations. Motor involvement is present in all advanced cases and can be severe. After age 20 years, the distal wasting and weakness may involve proximal muscles, possibly leading to wheelchair dependency by the seventh or eighth decade. Sensorineural hearing loss is variable. Diagnosis/testing. The diagnosis of SPTLC1 -related HSN is established in a proband with characteristic clinical features and identification of a heterozygous pathogenic variant in SPTLC1 on molecular genetic testing.
In sporadic cases, acquired neuropathies, such as the diabetic foot syndrome and alcoholic neuropathy , can be excluded by the use of magnetic resonance imaging and by interdisciplinary discussion between neurologists, dermatologists, and orthopedics. [1] [2] The diagnosis of the disease has been revolutionized by the identification of the causative genes. ... In dermatological literature, the term Thèvenard syndrome is still used for familial forms, whereas Bureau-Barrière syndrome is for sporadic forms. [41] In 1975, Dyck and Otha proposed a descriptive classification of the diseases and introduced the term hereditary sensory neuropathy (HSN) which later was changed to hereditary sensory and autonomic neuropathy (HSAN) given the substantial autonomic involvement in the diseases. [3] The diseases were categorized into five types HSAN I-V based on the mode of inheritance, the predominant clinical features, and the age at onset .
A number sign (#) is used with this entry because of evidence that hereditary sensory neuropathy type IF (HSN1F) is caused by heterozygous mutation in the ATL3 gene (609369) on chromosome 11q13. Description Hereditary sensory neuropathy type IF is an autosomal dominant sensory neuropathy affecting the lower limbs. Distal sensory impairment becomes apparent during the second or third decade of life, resulting in painless ulceration of the feet with poor healing, which can progress to osteomyelitis, bone destruction, and amputation. There is no autonomic involvement, spasticity, or cognitive impairment (summary by Kornak et al., 2014). For a discussion of genetic heterogeneity of HSN, see HSAN1A (162400).
A number sign (#) is used with this entry because hereditary sensory and autonomic neuropathy type IC (HSAN1C) is caused by heterozygous mutation in the SPTLC2 gene (605713) gene on chromosome 14q24. For a discussion of genetic heterogeneity of HSAN, see HSAN1A (162400). Clinical Features Rotthier et al. (2010) reported 4 unrelated probands with hereditary sensory neuropathy. Three probands had adult onset (ages 38, 37, and 52 years) of distal sensory loss. The presenting symptoms in these patients included loss of touch and vibration in the feet, dysesthesia and severe panmodal sensory loss in the upper and lower limbs, and distal lower limb sensory loss with ulceration and osteomyelitis necessitating amputation of the right great toe.
A number sign (#) is used with this entry because hereditary sensory neuropathy type IA (HSAN1A) is caused by heterozygous mutation in the SPTLC1 gene (605712) on chromosome 9q22. Description The hereditary sensory and autonomic neuropathies (HSAN), which are also referred to as hereditary sensory neuropathies (HSN) in the absence of significant autonomic features, are a genetically and clinically heterogeneous group of disorders associated with sensory dysfunction. HSAN1 is a dominantly inherited sensorimotor axonal neuropathy with onset in the first or second decades of life. Genetic Heterogeneity of Hereditary Sensory and Autonomic Neuropathy See also HSAN1C (613640), caused by mutation in the SPTLC2 gene (605713) on 14q24; HSN1D (613708), caused by mutation in the ATL1 gene (606439) on 14q; HSN1E (614116), caused by mutation in the DNMT1 gene (126375) on 19p13; HSN1F (615632), caused by mutation in the ATL3 gene (609369) on 11q13; HSAN2A (201300), caused by mutation in the HSN2 isoform of the WNK1 gene (605232) on 12p13; HSAN2B (613115), caused by mutation in the FAM134B gene (613114) on 5p15; HSN2C (614213), caused by mutation in the KIF1A gene (601255) on 2q37; HSAN2D (see 243000), caused by mutation in the SCN9A gene (603415) on 2q24; HSAN3 (223900), caused by mutation in the IKBKAP gene (603722) on 9q31; HSAN4 (256800), caused by mutation in the NTRK1 gene (191315) on 1q23; HSAN5 (608654), caused by mutation in the NGF gene (162030) on 1p13; HSAN6 (614653), caused by mutation in the DST gene (113810) on 6p; HSAN7 (615548), caused by mutation in the SCN11A gene (604385) on 3p22; and HSAN8 (616488), caused by mutation in the PRDM12 gene (616458) on chromosome 9q34. Adult-onset HSAN with anosmia (608720) is believed to be another distinct form of HSAN, and HSAN1B (608088) with cough and gastroesophageal reflux maps to chromosome 3p24-p22.
A number sign (#) is used with this entry because autosomal dominant hereditary sensory neuropathy type 1D (HSN1D) is caused by heterozygous mutation in the atlastin-1 gene (ATL1; 606439) on chromosome 14q. Description Autosomal dominant hereditary sensory neuropathy type 1D is characterized by adult onset of a distal axonal sensory neuropathy affecting all modalities, often associated with distal ulceration and amputation as well as hyporeflexia, although some patients may show features suggesting upper neuron involvement (summary by Guelly et al., 2011). For a discussion of genetic heterogeneity of HSAN, see HSAN1A (162400). Spastic paraplegia-3A (SPG3A; 182600) is an allelic disorder with a different phenotype. Clinical Features Guelly et al. (2011) reported a 4-generation family with hereditary sensory neuropathy inherited in an autosomal dominant pattern.
Hereditary sensory neuropathy type 1 (HSN1) is a neurological condition characterized by nerve abnormalities in the legs and feet. Many people with this condition have tingling, weakness, and a reduced ability to feel pain and sense hot and cold. Some affected people do not lose sensation, but instead feel shooting pains in their legs and feet. As HSN1 progresses, sensory problems can affect the hands, arms, shoulders, and abdomen. In rare cases, people with this condition develop sensorineural hearing loss.
A rare primary headache disorder characterized by multiple attacks of unilateral pain that occur in association with ipsilateral cranial autonomic symptoms. The hallmarks of this syndrome are the relative shortness of the attacks and the complete response to indomethacin therapy.
Differential diagnosis Differential diagnoses include Huntington disease and spinocerebellar ataxia type 17 (see these terms), although neither has the characteristic findings on neuroimaging; choreoacanthocytosis and McLeod neuroacanthocytosis syndrome (see these terms), although, unlike in these two diseases, the reflexes are preserved in neuroferritinopathy, and juvenile-onset Parkinson disease, aceruloplasminemia and Neimann-Pick type C (see these terms), although these disorders do not show the characteristic neuroimaging of neuroferritinopathy.
Thus, mutations in the light chain of ferritin result in the accumulation of iron in the brain which can be imaged using MRI . [2] Currently, neuroferritinopathy is the only neurodegenerative disease with an iron accumulation in the brain classified as an autosomal dominant syndrome. [4] Treatment of neuroferritinopathy is focused on managing symptoms associated with chorea and dystonia using standard medications for each. [2] The disorder is progressive and symptoms become worse with age. ... Classification [ edit ] All brain iron disorders were previously labeled pantothenate kinase-associated neurodegeneration formerly known as Hallervorden-Spatz syndrome, after the scientists who first discovered individuals with abnormal iron levels in 1922 (subsequently renamed after discovering their Nazi party ties). [1] Brain iron disorders are now divided into three categories: genetic neurodegeneration with brain iron accumulation, genetic systemic iron accumulation with neurologic features, and acquired diseases associated with iron excess or iron deficiency.
Neuroferritinopathy is a disorder in which iron gradually accumulates in the brain. Certain brain regions that help control movement (basal ganglia) are particularly affected. People with neuroferritinopathy have progressive problems with movement that begin at about age 40. These movement problems can include involuntary jerking motions (chorea), rhythmic shaking (tremor), difficulty coordinating movements (ataxia), or uncontrolled tensing of muscles (dystonia). Symptoms of the disorder may be more apparent on one side of the body than on the other.
Spinocerebellar ataxia type 17 (SCA17) TBP AD Family history consistent w/AD inheritance Spasticity (absent in neuroferritinopathy) Early-onset primary dystonia (DYT1) TOR1A 1 AD Generalized dystonia Chorea uncommon; no psychiatric features Chorea-acanthocytosis VPS13A AR Orofacial dyskinesia Impaired reflexes (preserved in neuroferritinopathy) McLeod neuroacanthocytosis syndrome XK XL Orofacial dyskinesia Absent deep tendon reflexes (preserved in neuroferritinopathy) SCA2 ATXN2 AD Dystonia Ataxia & neuropathy (a minor feature & absent, respectively, in neuroferritinopathy) SCA3 ATXN3 AD Dystonia, chorea, orofacial movement disorder Spasticity (absent in neuroferritinopathy) Parkin-type of juvenile-onset Parkinson disease PRKN AR Early-onset movement disorder Different MRI findings Aceruloplasminemia CP AR Early-onset movement disorder Different MRI findings Neimann-Pick type C NPC1 NPC2 AR Early-onset movement disorder Different MRI findings Pantothenate kinase-associated neurodegeneration PANK2 AR Very similar MRI findings incl "eye of the tiger" sign AR inheritance; earlier onset Mitochondrial disorders (see Mitochondrial Disease Overview) Various Various Basal ganglia abnormalities on MRI Different MRI findings Infantile neuroaxonal dystrophy PLA2G6 AR Imaging findings resembling but distinct from neuroferritinopathy AR inheritance; earlier onset AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; MOI = mode of inheritance; XL = X-linked 1.
Neuroferritinopathy is a movement disorder caused by the gradual accumulation of iron in the basal ganglia of the brain. People with neuroferritinopathy have progressive problems with movement that begin at about age 40. These movement problems can include involuntary jerking motions ( chorea ), rhythmic shaking ( tremor ), difficulty coordinating movements (ataxia), or uncontrolled tensing of muscles (dystonia). Symptoms of the disorder may be more prominent on one side of the body. Affected individuals may also have difficulty swallowing (dysphagia) and speaking (dysarthria).
Two affected members had a frontal lobe syndrome, and 1 had dementia. MRI of 3 affected family members showed cystic changes in the basal ganglia. ... In a healthy 52-year-old woman who was a control subject in a genetic study of hyperferritinemia-cataract syndrome, Cremonesi et al. (2004) identified a heterozygous mutation in the ATG start codon of the FTL gene (M1V; 134790.0018), predicted to disable protein translation and expression.
The combination of extreme pain severity and longevity can contribute to chronic depression and even suicide. [1] [2] See also [ edit ] Ramsay Hunt syndrome type 2 Postherpetic neuralgia References [ edit ] ^ Gilden, D.
It is a common feature of hypochondriasis and is commonly found with fibromyalgia , major depressive disorder , some anxiety disorders , Asperger syndrome , and alexithymia . [1] [2] [3] [4] One common clinical measure of SA is the Somatosensory Amplification Scale (SSAS).