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Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities(NEDSWMA; CPSQ1, FORMERLY)

MedGen UID:
1736667
Concept ID:
C5436628
Disease or Syndrome
Synonym: Cerebral palsy, spastic quadriplegic, 1
 
Gene (location): HPDL (1p34.1)
 
Monarch Initiative: MONDO:0033613
OMIM®: 619026

Definition

Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA) is an autosomal recessive disorder characterized by impaired psychomotor development apparent in infancy. Affected individuals show poor overall growth, progressive microcephaly, and axial hypotonia, with later onset of spasticity. The disorder is progressive. Some patients show normal early development, but later have regression of motor, cognitive, and language skills. More variable features include seizures, joint contractures, ocular disturbances, episodic respiratory failure, and nonspecific dysmorphic facial features. The intellectual impairment is variable, ranging from poor visual contact with inability to walk or speak to milder intellectual disability with the ability to say some words. Brain imaging shows variable white matter abnormalities, including thin corpus callosum and poor myelination (summary by Husain et al., 2020). [from OMIM]

Clinical features

From HPO
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
Failure to thrive in infancy
MedGen UID:
358083
Concept ID:
C1867873
Finding
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.
Spastic paraplegia
MedGen UID:
20882
Concept ID:
C0037772
Disease or Syndrome
Spasticity and weakness of the leg and hip muscles.
Hypoplasia of the corpus callosum
MedGen UID:
138005
Concept ID:
C0344482
Congenital Abnormality
Underdevelopment of the corpus callosum.
Abnormal cerebral white matter morphology
MedGen UID:
181756
Concept ID:
C0948163
Pathologic Function
An abnormality of the cerebral white matter.
Increased CSF lactate
MedGen UID:
257904
Concept ID:
C1167918
Finding
Increased concentration of lactate in the cerebrospinal fluid.
Axial dystonia
MedGen UID:
373027
Concept ID:
C1836149
Finding
A type of dystonia that affects the midline muscles, i.e., the chest, abdominal, and back muscles.
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
Decreased sensory nerve conduction velocity
MedGen UID:
336512
Concept ID:
C1849148
Finding
Reduced speed of conduction of the action potential along a sensory nerve.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Decreased motor nerve conduction velocity
MedGen UID:
388130
Concept ID:
C1858729
Finding
A type of decreased nerve conduction velocity that affects the motor 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.
Elevated brain lactate level by MRS
MedGen UID:
868368
Concept ID:
C4022762
Finding
An increase in the level of lactate in the brain identified by magnetic resonance spectroscopy (MRS).
Retrognathia
MedGen UID:
19766
Concept ID:
C0035353
Congenital Abnormality
An abnormality in which the mandible is mislocalised posteriorly.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Flexion contracture
MedGen UID:
83069
Concept ID:
C0333068
Anatomical Abnormality
A flexion contracture is a bent (flexed) joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.
Increased variability in muscle fiber diameter
MedGen UID:
336019
Concept ID:
C1843700
Finding
An abnormally high degree of muscle fiber size variation. This phenotypic feature can be observed upon muscle biopsy.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Respiratory failure requiring assisted ventilation
MedGen UID:
870821
Concept ID:
C4025279
Finding
A state of respiratory distress that requires a life saving intervention in the form of gaining airway access and instituting positive pressure ventilation.
Increased circulating lactate concentration
MedGen UID:
332209
Concept ID:
C1836440
Finding
Abnormally increased level of blood lactate (2-hydroxypropanoic acid). Lactate is produced from pyruvate by lactate dehydrogenase during normal metabolism. The terms lactate and lactic acid are often used interchangeably but lactate (the component measured in blood) is strictly a weak base whereas lactic acid is the corresponding acid. Lactic acidosis is often used clinically to describe elevated lactate but should be reserved for cases where there is a corresponding acidosis (pH below 7.35).
Drooling
MedGen UID:
8484
Concept ID:
C0013132
Finding
Habitual flow of saliva out of the mouth.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Short neck
MedGen UID:
99267
Concept ID:
C0521525
Finding
Diminished length of the neck.
Anteverted nares
MedGen UID:
326648
Concept ID:
C1840077
Finding
Anteriorly-facing nostrils viewed with the head in the Frankfurt horizontal and the eyes of the observer level with the eyes of the subject. This gives the appearance of an upturned nose (upturned nasal tip).
Long philtrum
MedGen UID:
351278
Concept ID:
C1865014
Finding
Distance between nasal base and midline upper lip vermilion border more than 2 SD above the mean. Alternatively, an apparently increased distance between nasal base and midline upper lip vermilion border.
Long eyelashes
MedGen UID:
342955
Concept ID:
C1853738
Finding
Mid upper eyelash length >10 mm or increased length of the eyelashes (subjective).
Esotropia
MedGen UID:
4550
Concept ID:
C0014877
Disease or Syndrome
A form of strabismus with one or both eyes turned inward ('crossed') to a relatively severe degree, usually defined as 10 diopters or more.
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).
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.
External ophthalmoplegia
MedGen UID:
57662
Concept ID:
C0162292
Disease or Syndrome
Paralysis of the external ocular muscles.
Visual impairment
MedGen UID:
777085
Concept ID:
C3665347
Finding
Visual impairment (or vision impairment) is vision loss (of a person) to such a degree as to qualify as an additional support need through a significant limitation of visual capability resulting from either disease, trauma, or congenital or degenerative conditions that cannot be corrected by conventional means, such as refractive correction, medication, or surgery.
Exodeviation
MedGen UID:
1637525
Concept ID:
C4551670
Disease or Syndrome
A manifest or latent ocular deviation in which one or both eyes tends to deviate temporally.
Esodeviation
MedGen UID:
1641033
Concept ID:
C4551734
Disease or Syndrome
A manifest or latent ocular deviation in which one or both eyes tends to deviate nasally.

Professional guidelines

PubMed

O'Shea TM
Clin Obstet Gynecol 2008 Dec;51(4):816-28. doi: 10.1097/GRF.0b013e3181870ba7. PMID: 18981805Free PMC Article

Recent clinical studies

Etiology

Nakamura Y, Okanishi T, Yamada H, Okazaki T, Hosoda C, Itai T, Miyatake S, Saitsu H, Matsumoto N, Maegaki Y
Brain Dev 2021 Nov;43(10):1033-1038. Epub 2021 Jul 17 doi: 10.1016/j.braindev.2021.06.008. PMID: 34281745
Bosley TM, Salih MA, Alorainy IA, Islam MZ, Oystreck DT, Suliman OS, al Malki S, Suhaibani AH, Khiari H, Beckers S, van Wesenbeeck L, Perdu B, AlDrees A, Elmalik SA, Van Hul W, Abu-Amero KK
Brain 2011 Dec;134(Pt 12):3502-15. Epub 2011 Nov 26 doi: 10.1093/brain/awr302. PMID: 22120147
O'Shea TM
Clin Obstet Gynecol 2008 Dec;51(4):816-28. doi: 10.1097/GRF.0b013e3181870ba7. PMID: 18981805Free PMC Article
Mitchell W
Ment Retard Dev Disabil Res Rev 2001;7(3):211-6. doi: 10.1002/mrdd.1029. PMID: 11553937
Kristjánsdóttir R, Uvebrant P, Wiklund LM
Eur J Paediatr Neurol 2000;4(1):17-26. doi: 10.1053/ejpn.1999.0255. PMID: 10701100

Diagnosis

Kavanaugh BC, Warren EB, Baytas O, Schmidt M, Merck D, Buch K, Liu JS, Phornphutkul C, Caruso P, Morrow EM
Am J Med Genet A 2019 Nov;179(11):2284-2291. Epub 2019 Aug 12 doi: 10.1002/ajmg.a.61322. PMID: 31403263Free PMC Article
Õiglane-Shlik E, Puusepp S, Talvik I, Vaher U, Rein R, Tammur P, Reimand T, Teek R, Žilina O, Tomberg T, Õunap K
Eur J Paediatr Neurol 2014 May;18(3):338-46. Epub 2014 Jan 25 doi: 10.1016/j.ejpn.2014.01.008. PMID: 24529875
O'Shea TM
Clin Obstet Gynecol 2008 Dec;51(4):816-28. doi: 10.1097/GRF.0b013e3181870ba7. PMID: 18981805Free PMC Article
Mitchell W
Ment Retard Dev Disabil Res Rev 2001;7(3):211-6. doi: 10.1002/mrdd.1029. PMID: 11553937
Kristjánsdóttir R, Uvebrant P, Wiklund LM
Eur J Paediatr Neurol 2000;4(1):17-26. doi: 10.1053/ejpn.1999.0255. PMID: 10701100

Therapy

Bosley TM, Salih MA, Alorainy IA, Islam MZ, Oystreck DT, Suliman OS, al Malki S, Suhaibani AH, Khiari H, Beckers S, van Wesenbeeck L, Perdu B, AlDrees A, Elmalik SA, Van Hul W, Abu-Amero KK
Brain 2011 Dec;134(Pt 12):3502-15. Epub 2011 Nov 26 doi: 10.1093/brain/awr302. PMID: 22120147

Prognosis

Saffari A, Lau T, Tajsharghi H, Karimiani EG, Kariminejad A, Efthymiou S, Zifarelli G, Sultan T, Toosi MB, Sedighzadeh S, Siu VM, Ortigoza-Escobar JD, AlShamsi AM, Ibrahim S, Al-Sannaa NA, Al-Hertani W, Sandra W, Tarnopolsky M, Alavi S, Li C, Day-Salvatore DL, Martínez-González MJ, Levandoski KM, Bedoukian E, Madan-Khetarpal S, Idleburg MJ, Menezes MJ, Siddharth A, Platzer K, Oppermann H, Smitka M, Collins F, Lek M, Shahrooei M, Ghavideldarestani M, Herman I, Rendu J, Faure J, Baker J, Bhambhani V, Calderwood L, Akhondian J, Imannezhad S, Mirzadeh HS, Hashemi N, Doosti M, Safi M, Ahangari N, Torbati PN, Abedini S, Salpietro V, Gulec EY, Eshaghian S, Ghazavi M, Pascher MT, Vogel M, Abicht A, Moutton S, Bruel AL, Rieubland C, Gallati S, Strom TM, Lochmüller H, Mohammadi MH, Alvi JR, Zackai EH, Keena BA, Skraban CM, Berger SI, Andrew EH, Rahimian E, Morrow MM, Wentzensen IM, Millan F, Henderson LB, Dafsari HS, Jungbluth H, Gomez-Ospina N, McRae A, Peter M, Veltra D, Marinakis NM, Sofocleous C, Ashrafzadeh F, Pehlivan D, Lemke JR, Melki J, Benezit A, Bauer P, Weis D, Lupski JR, Senderek J, Christodoulou J, Chung WK, Goodchild R, Offiah AC, Moreno-De-Luca A, Suri M, Ebrahimi-Fakhari D, Houlden H, Maroofian R
Brain 2023 Aug 1;146(8):3273-3288. doi: 10.1093/brain/awad039. PMID: 36757831Free PMC Article
Bosley TM, Salih MA, Alorainy IA, Islam MZ, Oystreck DT, Suliman OS, al Malki S, Suhaibani AH, Khiari H, Beckers S, van Wesenbeeck L, Perdu B, AlDrees A, Elmalik SA, Van Hul W, Abu-Amero KK
Brain 2011 Dec;134(Pt 12):3502-15. Epub 2011 Nov 26 doi: 10.1093/brain/awr302. PMID: 22120147
O'Shea TM
Clin Obstet Gynecol 2008 Dec;51(4):816-28. doi: 10.1097/GRF.0b013e3181870ba7. PMID: 18981805Free PMC Article
Mitchell W
Ment Retard Dev Disabil Res Rev 2001;7(3):211-6. doi: 10.1002/mrdd.1029. PMID: 11553937
Kristjánsdóttir R, Uvebrant P, Wiklund LM
Eur J Paediatr Neurol 2000;4(1):17-26. doi: 10.1053/ejpn.1999.0255. PMID: 10701100

Clinical prediction guides

Akahoshi K, Nakagawa E, Goto YI, Inoue K
BMC Med Genomics 2023 Mar 6;16(1):43. doi: 10.1186/s12920-023-01465-3. PMID: 36879246Free PMC Article
Saffari A, Lau T, Tajsharghi H, Karimiani EG, Kariminejad A, Efthymiou S, Zifarelli G, Sultan T, Toosi MB, Sedighzadeh S, Siu VM, Ortigoza-Escobar JD, AlShamsi AM, Ibrahim S, Al-Sannaa NA, Al-Hertani W, Sandra W, Tarnopolsky M, Alavi S, Li C, Day-Salvatore DL, Martínez-González MJ, Levandoski KM, Bedoukian E, Madan-Khetarpal S, Idleburg MJ, Menezes MJ, Siddharth A, Platzer K, Oppermann H, Smitka M, Collins F, Lek M, Shahrooei M, Ghavideldarestani M, Herman I, Rendu J, Faure J, Baker J, Bhambhani V, Calderwood L, Akhondian J, Imannezhad S, Mirzadeh HS, Hashemi N, Doosti M, Safi M, Ahangari N, Torbati PN, Abedini S, Salpietro V, Gulec EY, Eshaghian S, Ghazavi M, Pascher MT, Vogel M, Abicht A, Moutton S, Bruel AL, Rieubland C, Gallati S, Strom TM, Lochmüller H, Mohammadi MH, Alvi JR, Zackai EH, Keena BA, Skraban CM, Berger SI, Andrew EH, Rahimian E, Morrow MM, Wentzensen IM, Millan F, Henderson LB, Dafsari HS, Jungbluth H, Gomez-Ospina N, McRae A, Peter M, Veltra D, Marinakis NM, Sofocleous C, Ashrafzadeh F, Pehlivan D, Lemke JR, Melki J, Benezit A, Bauer P, Weis D, Lupski JR, Senderek J, Christodoulou J, Chung WK, Goodchild R, Offiah AC, Moreno-De-Luca A, Suri M, Ebrahimi-Fakhari D, Houlden H, Maroofian R
Brain 2023 Aug 1;146(8):3273-3288. doi: 10.1093/brain/awad039. PMID: 36757831Free PMC Article
O'Shea TM
Clin Obstet Gynecol 2008 Dec;51(4):816-28. doi: 10.1097/GRF.0b013e3181870ba7. PMID: 18981805Free PMC Article
Mitchell W
Ment Retard Dev Disabil Res Rev 2001;7(3):211-6. doi: 10.1002/mrdd.1029. PMID: 11553937

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