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Infantile neuroaxonal dystrophy(NBIA2A)

MedGen UID:
82852
Concept ID:
C0270724
Disease or Syndrome
Synonyms: Infantile neuroaxonal dystrophy 1; NBIA2A; NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 2A; Seitelberger disease
SNOMED CT: Seitelberger disease (52713000); INAD - Infantile neuroaxonal dystrophy (52713000); Infantile neuroaxonal dystrophy (52713000); Seitelberger's disease (52713000); Spastic amaurotic axonal idiocy (52713000)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): PLA2G6 (22q13.1)
 
Monarch Initiative: MONDO:0024457
OMIM®: 256600
Orphanet: ORPHA35069

Definition

PLA2G6-associated neurodegeneration (PLAN) comprises a continuum of three phenotypes with overlapping clinical and radiologic features: Infantile neuroaxonal dystrophy (INAD). Atypical neuroaxonal dystrophy (atypical NAD). PLA2G6-related dystonia-parkinsonism. INAD usually begins between ages six months and three years with psychomotor regression or delay, hypotonia, and progressive spastic tetraparesis. Many affected children never learn to walk or lose the ability shortly after attaining it. Strabismus, nystagmus, and optic atrophy are common. Disease progression is rapid, resulting in severe spasticity, progressive cognitive decline, and visual impairment. Many affected children do not survive beyond their first decade. Atypical NAD shows more phenotypic variability than INAD. In general, onset is in early childhood but can be as late as the end of the second decade. The presenting signs may be gait instability, ataxia, or speech delay and autistic features, which are sometimes the only evidence of disease for a year or more. Strabismus, nystagmus, and optic atrophy are common. Neuropsychiatric disturbances including impulsivity, poor attention span, hyperactivity, and emotional lability are also common. The course is fairly stable during early childhood and resembles static encephalopathy but is followed by neurologic deterioration between ages seven and 12 years. PLA2G6-related dystonia-parkinsonism has a variable age of onset, but most individuals present in early adulthood with gait disturbance or neuropsychiatric changes. Affected individuals consistently develop dystonia and parkinsonism (which may be accompanied by rapid cognitive decline) in their late teens to early twenties. Dystonia is most common in the hands and feet but may be more generalized. The most common features of parkinsonism in these individuals are bradykinesia, resting tremor, rigidity, and postural instability. [from GeneReviews]

Additional description

From MedlinePlus Genetics
Infantile neuroaxonal dystrophy is a disorder that primarily affects the nervous system. Individuals with infantile neuroaxonal dystrophy typically do not have any symptoms at birth, but between the ages of about 6 and 18 months they begin to experience delays in acquiring new motor and intellectual skills, such as crawling or beginning to speak. Eventually they lose previously acquired skills (developmental regression). In some cases, signs and symptoms of infantile neuroaxonal dystrophy first appear later in childhood or during the teenage years and progress more slowly.

Children with infantile neuroaxonal dystrophy experience progressive difficulties with movement. They generally have muscles that are at first weak and "floppy" (hypotonic), and then gradually become very stiff (spastic). Eventually, affected children lose the ability to move independently. Lack of muscle strength causes difficulty with feeding. Muscle weakness can also result in breathing problems that can lead to frequent infections, such as pneumonia. Seizures occur in some affected children.

Rapid, involuntary eye movements (nystagmus), eyes that do not look in the same direction (strabismus), and vision loss due to deterioration (atrophy) of the nerve that carries information from the eye to the brain (the optic nerve) often occur in infantile neuroaxonal dystrophy. Hearing loss may also develop. Children with this disorder experience progressive deterioration of cognitive functions (dementia), and they eventually lose awareness of their surroundings.

Infantile neuroaxonal dystrophy is characterized by the development of swellings called spheroid bodies in the axons, the fibers that extend from nerve cells (neurons) and transmit impulses to muscles and other neurons. In some individuals with infantile neuroaxonal dystrophy, abnormal amounts of iron accumulate in a specific region of the brain called the basal ganglia. The relationship of these features to the symptoms of infantile neuroaxonal dystrophy is unknown.  https://medlineplus.gov/genetics/condition/infantile-neuroaxonal-dystrophy

Clinical features

From HPO
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Gliosis
MedGen UID:
4899
Concept ID:
C0017639
Pathologic Function
Gliosis is the focal proliferation of glial cells in the central nervous system.
Neurodegeneration
MedGen UID:
17999
Concept ID:
C0027746
Cell or Molecular Dysfunction
Progressive loss of neural cells and tissue.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Unsteady gait
MedGen UID:
68544
Concept ID:
C0231686
Finding
A shaky or wobbly manner of walking.
Abnormal pyramidal sign
MedGen UID:
68582
Concept ID:
C0234132
Sign or Symptom
Functional neurological abnormalities related to dysfunction of the pyramidal tract.
Areflexia
MedGen UID:
115943
Concept ID:
C0234146
Finding
Absence of neurologic reflexes such as the knee-jerk reaction.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Spastic tetraplegia
MedGen UID:
98433
Concept ID:
C0426970
Disease or Syndrome
Spastic paralysis affecting all four limbs.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Abnormality of visual evoked potentials
MedGen UID:
105509
Concept ID:
C0522214
Finding
An anomaly of visually evoked potentials (VEP), which are electrical potentials, initiated by brief visual stimuli, which are recorded from the scalp overlying the visual cortex.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
Neuronal loss in central nervous system
MedGen UID:
342515
Concept ID:
C1850496
Finding
Decreased nerve conduction velocity
MedGen UID:
347509
Concept ID:
C1857640
Finding
A reduction in the speed at which electrical signals propagate along the axon of a neuron.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Iron accumulation in brain
MedGen UID:
866729
Concept ID:
C4021076
Finding
An abnormal build up of iron (Fe) in brain tissue.
Abnormal pyramidal tract morphology
MedGen UID:
892809
Concept ID:
C4021761
Anatomical Abnormality
Any structural abnormality of the pyramidal tract, whose chief element, the corticospinal tract, is the only direct connection between the brain and the spinal cord. In addition to the corticospinal tract, the pyramidal system includes the corticobulbar, corticomesencephalic, and corticopontine tracts.
Reduced social responsiveness
MedGen UID:
868342
Concept ID:
C4022736
Finding
A reduced ability to participate in the back-and-forth flow of social interaction appropriate to culture and developmental level, which is normally characterized by an influence of the behavior of one person on the behavior of another person. This results in difficulty interacting with others through emotional, physical, or verbal communication.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.
Generalized muscle weakness
MedGen UID:
155433
Concept ID:
C0746674
Sign or Symptom
Generalized weakness or decreased strength of the muscles, affecting both distal and proximal musculature.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
EMG: chronic denervation signs
MedGen UID:
871143
Concept ID:
C4025614
Finding
Evidence of chronic denervation on electromyography.
Prominent forehead
MedGen UID:
373291
Concept ID:
C1837260
Finding
Forward prominence of the entire forehead, due to protrusion of the frontal bone.
Short nose
MedGen UID:
343052
Concept ID:
C1854114
Finding
Distance from nasion to subnasale more than two standard deviations below the mean, or alternatively, an apparently decreased length from the nasal root to the nasal tip.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.
Visual loss
MedGen UID:
784038
Concept ID:
C3665386
Finding
Loss of visual acuity (implying that vision was better at a certain time point in life). Otherwise the term reduced visual acuity should be used (or a subclass of that).

Professional guidelines

PubMed

Gong WD, Tao G, Zhao TT, Yang Y, Ji H
Yi Chuan 2023 Jul 20;45(7):617-623. doi: 10.16288/j.yczz.23-034. PMID: 37503585
Xue J, Ding DX, Xu GY, Wang PZ, Ge YL, Zhang JR, Cheng XY, Wang YM, Jin H, Luo SY, Zheng YH, Chen J, Wang F, Li D, Mao CJ, Li K, Liu CF
Parkinsonism Relat Disord 2023 Jul;112:105477. Epub 2023 Jun 1 doi: 10.1016/j.parkreldis.2023.105477. PMID: 37285793
Nardocci N, Zorzi G, Farina L, Binelli S, Scaioli W, Ciano C, Verga L, Angelini L, Savoiardo M, Bugiani O
Neurology 1999 Apr 22;52(7):1472-8. doi: 10.1212/wnl.52.7.1472. PMID: 10227637

Recent clinical studies

Etiology

Deng X, Yuan L, Jankovic J, Deng H
Ageing Res Rev 2023 Aug;89:101957. Epub 2023 May 24 doi: 10.1016/j.arr.2023.101957. PMID: 37236368
Hayflick SJ, Kurian MA, Hogarth P
Handb Clin Neurol 2018;147:293-305. doi: 10.1016/B978-0-444-63233-3.00019-1. PMID: 29325618Free PMC Article
Iodice A, Spagnoli C, Salerno GG, Frattini D, Bertani G, Bergonzini P, Pisani F, Fusco C
Brain Dev 2017 Feb;39(2):93-100. Epub 2016 Nov 21 doi: 10.1016/j.braindev.2016.08.012. PMID: 27884548
Nardocci N, Zorzi G
Handb Clin Neurol 2013;113:1919-24. doi: 10.1016/B978-0-444-59565-2.00062-9. PMID: 23622415
Yiu EM, Ryan MM
J Peripher Nerv Syst 2012 Sep;17(3):285-300. doi: 10.1111/j.1529-8027.2012.00412.x. PMID: 22971091

Diagnosis

Hayflick SJ, Kurian MA, Hogarth P
Handb Clin Neurol 2018;147:293-305. doi: 10.1016/B978-0-444-63233-3.00019-1. PMID: 29325618Free PMC Article
Iodice A, Spagnoli C, Salerno GG, Frattini D, Bertani G, Bergonzini P, Pisani F, Fusco C
Brain Dev 2017 Feb;39(2):93-100. Epub 2016 Nov 21 doi: 10.1016/j.braindev.2016.08.012. PMID: 27884548
Nardocci N, Zorzi G
Handb Clin Neurol 2013;113:1919-24. doi: 10.1016/B978-0-444-59565-2.00062-9. PMID: 23622415
Yiu EM, Ryan MM
J Peripher Nerv Syst 2012 Sep;17(3):285-300. doi: 10.1111/j.1529-8027.2012.00412.x. PMID: 22971091
Rees H, Ang LC, Casey R, George DH
Pediatr Neurosurg 1995;22(6):321-7. doi: 10.1159/000120923. PMID: 7577667

Therapy

Kanda PA, Kanda RG, Mei PA, Cury IJ
Neurodiagn J 2015 Dec;55(4):235-42. doi: 10.1080/21646821.2015.1092779. PMID: 26793900
Dachy B, Dan B
Clin Neurophysiol 2002 Mar;113(3):336-40. doi: 10.1016/s1388-2457(02)00010-x. PMID: 11897533

Prognosis

Gong WD, Tao G, Zhao TT, Yang Y, Ji H
Yi Chuan 2023 Jul 20;45(7):617-623. doi: 10.16288/j.yczz.23-034. PMID: 37503585
Altuame FD, Foskett G, Atwal PS, Endemann S, Midei M, Milner P, Salih MA, Hamad M, Al-Muhaizea M, Hashem M, Alkuraya FS
Orphanet J Rare Dis 2020 May 1;15(1):109. doi: 10.1186/s13023-020-01355-2. PMID: 32357911Free PMC Article
Nardocci N, Zorzi G
Handb Clin Neurol 2013;113:1919-24. doi: 10.1016/B978-0-444-59565-2.00062-9. PMID: 23622415
Rees H, Ang LC, Casey R, George DH
Pediatr Neurosurg 1995;22(6):321-7. doi: 10.1159/000120923. PMID: 7577667
Aicardi J, Castelein P
Brain 1979 Dec;102(4):727-48. doi: 10.1093/brain/102.4.727. PMID: 509195

Clinical prediction guides

Gong WD, Tao G, Zhao TT, Yang Y, Ji H
Yi Chuan 2023 Jul 20;45(7):617-623. doi: 10.16288/j.yczz.23-034. PMID: 37503585
Xue J, Ding DX, Xu GY, Wang PZ, Ge YL, Zhang JR, Cheng XY, Wang YM, Jin H, Luo SY, Zheng YH, Chen J, Wang F, Li D, Mao CJ, Li K, Liu CF
Parkinsonism Relat Disord 2023 Jul;112:105477. Epub 2023 Jun 1 doi: 10.1016/j.parkreldis.2023.105477. PMID: 37285793
Atwal PS, Midei M, Adams D, Fay A, Heerinckx F, Milner P
Orphanet J Rare Dis 2020 Jul 29;15(1):195. doi: 10.1186/s13023-020-01479-5. PMID: 32727524Free PMC Article
Altuame FD, Foskett G, Atwal PS, Endemann S, Midei M, Milner P, Salih MA, Hamad M, Al-Muhaizea M, Hashem M, Alkuraya FS
Orphanet J Rare Dis 2020 May 1;15(1):109. doi: 10.1186/s13023-020-01355-2. PMID: 32357911Free PMC Article
Hayflick SJ, Kurian MA, Hogarth P
Handb Clin Neurol 2018;147:293-305. doi: 10.1016/B978-0-444-63233-3.00019-1. PMID: 29325618Free PMC Article

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