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Spinocerebellar ataxia, autosomal recessive 29(SCAR29; BAVAHAKA; NEDHCA)

MedGen UID:
1788435
Concept ID:
C5543595
Disease or Syndrome
Synonyms: BARAKAT-VAN HAM-KAYA SYNDROME; NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA AND CEREBELLAR ATAXIA
 
Gene (location): VPS41 (7p14.1)
 
Monarch Initiative: MONDO:0030312
OMIM®: 619389

Definition

Autosomal recessive spinocerebellar ataxia-29 (SCAR29) is a progressive neurodegenerative disorder characterized by delayed motor development in early infancy followed by difficulty walking due to an ataxic gait or inability to walk, hypotonia, and variably impaired intellectual development. Other features include dysarthria, nystagmus, peripheral spasticity, nystagmus, and visual impairment. Brain imaging typically shows atrophy of the cerebellar vermis, but other abnormalities may also be present. Some patients are wheelchair-bound and/or nonverbal (summary by Sanderson et al., 2021) In a review of the pathogenesis of disorders with prominent dystonia as a feature, Monfrini et al. (2021) classified SCAR29 as belonging to a group of neurologic disorders termed 'HOPS-associated neurologic disorders' (HOPSANDs), which are caused by mutations in genes encoding various components of the autophagic/endolysosomal system, including VPS41. [from OMIM]

Clinical features

From HPO
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).
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
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.
Corpus callosum atrophy
MedGen UID:
96560
Concept ID:
C0431370
Finding
The presence of atrophy (wasting) of the corpus callosum.
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.
Inability to walk
MedGen UID:
107860
Concept ID:
C0560046
Finding
Incapability to ambulate.
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.
Cerebellar vermis atrophy
MedGen UID:
149271
Concept ID:
C0742028
Disease or Syndrome
Wasting (atrophy) of the vermis of cerebellum.
Peripheral axonal neuropathy
MedGen UID:
266071
Concept ID:
C1263857
Disease or Syndrome
An abnormality characterized by disruption of the normal functioning of peripheral axons.
Lower limb spasticity
MedGen UID:
220865
Concept ID:
C1271100
Finding
Spasticity (velocity-dependent increase in tonic stretch reflexes with increased muscle tone and hyperexcitable tendon reflexes) in the muscles of the lower limbs, hips, and pelvis.
Generalized dystonia
MedGen UID:
341342
Concept ID:
C1848954
Finding
A type of dystonia that affects all or most of the body.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
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 substantia nigra
MedGen UID:
868391
Concept ID:
C4022785
Finding
An anomalous build up of iron (Fe) in the substantia nigra.
Eye of the tiger anomaly of globus pallidus
MedGen UID:
871224
Concept ID:
C4025705
Finding
The presence, on T2-weighted magnetic resonance imaging, of markedly low signal intensity of the globus pallidus that surrounds a central region of high signal intensity in the anteromedial globus pallidus, producing an eye-of-the-tiger appearance. The sign is thought to represent iron accumulation in the globus pallidus.
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.
Axial hypotonia
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.
Myopathic facies
MedGen UID:
90695
Concept ID:
C0332615
Finding
A facial appearance characteristic of myopathic conditions. The face appears expressionless with sunken cheeks, bilateral ptosis, and inability to elevate the corners of the mouth, due to muscle weakness.
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 disc pallor
MedGen UID:
108218
Concept ID:
C0554970
Finding
A pale yellow discoloration of the optic disc (the area of the optic nerve head in the retina). The optic disc normally has a pinkish hue with a central yellowish depression.
Retinal pigment epithelial mottling
MedGen UID:
347513
Concept ID:
C1857644
Finding
Mottling (spots or blotches with different shades) of the retinal pigment epithelium, i.e., localized or generalized fundal pigment granularity associated with processes at the level of the retinal pigment epithelium.

Professional guidelines

PubMed

De Castro M, García-Planells J, Monrós E, Cañizares J, Vázquez-Manrique R, Vílchez JJ, Urtasun M, Lucas M, Navarro G, Izquierdo G, Moltó MD, Palau F
Hum Genet 2000 Jan;106(1):86-92. doi: 10.1007/s004399900201. PMID: 10982187

Recent clinical studies

Etiology

Rezende Filho FM, Bremner F, Pedroso JL, de Andrade JBC, Marianelli BF, Lourenço CM, Marques-Júnior W, França MC Jr, Kok F, Sallum JMF, Parkinson MH, Barsottini OG, Giunti P
Mov Disord 2021 Sep;36(9):2027-2035. Epub 2021 Apr 23 doi: 10.1002/mds.28612. PMID: 33893680
Aghamohammadi A, Akrami SM, Yaghmaie M, Rezaei N, Azizi G, Yaseri M, Nosrati H, Zaki-Dizaji M
Sultan Qaboos Univ Med J 2018 Nov;18(4):e440-e446. Epub 2019 Mar 28 doi: 10.18295/squmj.2018.18.04.003. PMID: 30988961Free PMC Article
Pommerening H, van Dullemen S, Kieslich M, Schubert R, Zielen S, Voss S
Orphanet J Rare Dis 2015 Dec 9;10:155. doi: 10.1186/s13023-015-0373-z. PMID: 26645295Free PMC Article
Sahama I, Sinclair K, Fiori S, Pannek K, Lavin M, Rose S
Mov Disord 2014 Sep;29(10):1289-98. Epub 2014 Jul 17 doi: 10.1002/mds.25970. PMID: 25042086
Cabana MD, Crawford TO, Winkelstein JA, Christensen JR, Lederman HM
Pediatrics 1998 Jul;102(1 Pt 1):98-100. doi: 10.1542/peds.102.1.98. PMID: 9651420

Diagnosis

Milovanović A, Westenberger A, Stanković I, Tamaš O, Branković M, Marjanović A, Laabs BH, Brand M, Rajalingam R, Marras C, Lohmann K, Branković V, Novaković I, Petrović I, Svetel M, Klein C, Kostić VS, Dragašević-Mišković N
Mov Disord 2024 May;39(5):887-892. Epub 2024 Mar 12 doi: 10.1002/mds.29729. PMID: 38469933
Divya KP, Cherian A, Dhing HK, Kumar S, Thomas B, Faruq M
Acta Neurol Belg 2024 Apr;124(2):475-484. Epub 2023 Oct 29 doi: 10.1007/s13760-023-02400-0. PMID: 37898963
Rezende Filho FM, Bremner F, Pedroso JL, de Andrade JBC, Marianelli BF, Lourenço CM, Marques-Júnior W, França MC Jr, Kok F, Sallum JMF, Parkinson MH, Barsottini OG, Giunti P
Mov Disord 2021 Sep;36(9):2027-2035. Epub 2021 Apr 23 doi: 10.1002/mds.28612. PMID: 33893680
Briand MM, Rodrigue X, Lessard I, Mathieu J, Brais B, Côté I, Gagnon C
J Neurol Sci 2019 May 15;400:39-41. Epub 2019 Mar 12 doi: 10.1016/j.jns.2019.03.008. PMID: 30901567
Synofzik M, Soehn AS, Gburek-Augustat J, Schicks J, Karle KN, Schüle R, Haack TB, Schöning M, Biskup S, Rudnik-Schöneborn S, Senderek J, Hoffmann KT, MacLeod P, Schwarz J, Bender B, Krüger S, Kreuz F, Bauer P, Schöls L
Orphanet J Rare Dis 2013 Mar 15;8:41. doi: 10.1186/1750-1172-8-41. PMID: 23497566Free PMC Article

Therapy

Aghamohammadi A, Akrami SM, Yaghmaie M, Rezaei N, Azizi G, Yaseri M, Nosrati H, Zaki-Dizaji M
Sultan Qaboos Univ Med J 2018 Nov;18(4):e440-e446. Epub 2019 Mar 28 doi: 10.18295/squmj.2018.18.04.003. PMID: 30988961Free PMC Article
Pommerening H, van Dullemen S, Kieslich M, Schubert R, Zielen S, Voss S
Orphanet J Rare Dis 2015 Dec 9;10:155. doi: 10.1186/s13023-015-0373-z. PMID: 26645295Free PMC Article

Prognosis

Olsen JH, Hahnemann JM, Børresen-Dale AL, Tretli S, Kleinerman R, Sankila R, Hammarström L, Robsahm TE, Kääriäinen H, Bregård A, Brøndum-Nielsen K, Yuen J, Tucker M
Br J Cancer 2005 Jul 25;93(2):260-5. doi: 10.1038/sj.bjc.6602658. PMID: 15942625Free PMC Article
De Castro M, García-Planells J, Monrós E, Cañizares J, Vázquez-Manrique R, Vílchez JJ, Urtasun M, Lucas M, Navarro G, Izquierdo G, Moltó MD, Palau F
Hum Genet 2000 Jan;106(1):86-92. doi: 10.1007/s004399900201. PMID: 10982187
Athma P, Rappaport R, Swift M
Cancer Genet Cytogenet 1996 Dec;92(2):130-4. doi: 10.1016/s0165-4608(96)00328-7. PMID: 8976369

Clinical prediction guides

Elitzur S, Shiloh R, Loeffen JLC, Pastorczak A, Takagi M, Bomken S, Baruchel A, Lehrnbecher T, Tasian SK, Abla O, Arad-Cohen N, Astigarraga I, Ben-Harosh M, Bodmer N, Brozou T, Ceppi F, Chugaeva L, Dalla Pozza L, Ducassou S, Escherich G, Farah R, Gibson A, Hasle H, Hoveyan J, Jacoby E, Jazbec J, Junk S, Kolenova A, Lazic J, Lo Nigro L, Mahlaoui N, Miller L, Papadakis V, Pecheux L, Pillon M, Sarouk I, Stary J, Stiakaki E, Strullu M, Tran TH, Ussowicz M, Verdu-Amoros J, Wakulinska A, Zawitkowska J, Stoppa-Lyonnet D, Taylor AM, Shiloh Y, Izraeli S, Minard-Colin V, Schmiegelow K, Nirel R, Attarbaschi A, Borkhardt A
Blood 2024 Sep 12;144(11):1193-1205. doi: 10.1182/blood.2024024283. PMID: 38917355
Divya KP, Cherian A, Dhing HK, Kumar S, Thomas B, Faruq M
Acta Neurol Belg 2024 Apr;124(2):475-484. Epub 2023 Oct 29 doi: 10.1007/s13760-023-02400-0. PMID: 37898963
Rezende Filho FM, Bremner F, Pedroso JL, de Andrade JBC, Marianelli BF, Lourenço CM, Marques-Júnior W, França MC Jr, Kok F, Sallum JMF, Parkinson MH, Barsottini OG, Giunti P
Mov Disord 2021 Sep;36(9):2027-2035. Epub 2021 Apr 23 doi: 10.1002/mds.28612. PMID: 33893680
Wedding IM, Kroken M, Henriksen SP, Selmer KK, Fiskerstrand T, Knappskog PM, Berge T, Tallaksen CM
Orphanet J Rare Dis 2015 Sep 4;10:108. doi: 10.1186/s13023-015-0328-4. PMID: 26338206Free PMC Article
Synofzik M, Soehn AS, Gburek-Augustat J, Schicks J, Karle KN, Schüle R, Haack TB, Schöning M, Biskup S, Rudnik-Schöneborn S, Senderek J, Hoffmann KT, MacLeod P, Schwarz J, Bender B, Krüger S, Kreuz F, Bauer P, Schöls L
Orphanet J Rare Dis 2013 Mar 15;8:41. doi: 10.1186/1750-1172-8-41. PMID: 23497566Free PMC Article

Recent systematic reviews

Milovanović A, Westenberger A, Stanković I, Tamaš O, Branković M, Marjanović A, Laabs BH, Brand M, Rajalingam R, Marras C, Lohmann K, Branković V, Novaković I, Petrović I, Svetel M, Klein C, Kostić VS, Dragašević-Mišković N
Mov Disord 2024 May;39(5):887-892. Epub 2024 Mar 12 doi: 10.1002/mds.29729. PMID: 38469933

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