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Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome(PEBAT)

MedGen UID:
934638
Concept ID:
C4310671
Disease or Syndrome
Synonym: Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum
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): TBCD (17q25.3)
 
Monarch Initiative: MONDO:0044646
OMIM®: 617193
Orphanet: ORPHA496641

Definition

PEBAT is an autosomal recessive neurodevelopmental disorder characterized by severely delayed psychomotor development apparent soon after birth or in infancy, profound intellectual disability, poor or absent speech, and seizures. Most patients are never able to walk due to hypotonia or spasticity. Brain imaging shows cerebral and cerebellar atrophy, thin corpus callosum, and secondary hypomyelination. The disorder shows progressive features, including microcephaly, consistent with a neurodegenerative process (summary by Miyake et al., 2016; Flex et al., 2016). [from OMIM]

Clinical features

From HPO
Bowel incontinence
MedGen UID:
41977
Concept ID:
C0015732
Disease or Syndrome
Involuntary fecal soiling in adults and children who have usually already been toilet trained.
Urinary incontinence
MedGen UID:
22579
Concept ID:
C0042024
Finding
Loss of the ability to control the urinary bladder leading to involuntary urination.
Retractile testis
MedGen UID:
636075
Concept ID:
C0520578
Congenital Abnormality
A testis that is located at the upper scrotum or lower inguinal canal and that can be made to descend completely into the scrotum without resistance by manual reduction but returns to its original position by the cremasteric reflex.
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
Constipation
MedGen UID:
1101
Concept ID:
C0009806
Sign or Symptom
Infrequent or difficult evacuation of feces.
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Cataplexy
MedGen UID:
2862
Concept ID:
C0007384
Disease or Syndrome
A sudden and transient episode of bilateral loss of muscle tone, often triggered by emotions.
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.
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.
Encephalopathy
MedGen UID:
39314
Concept ID:
C0085584
Disease or Syndrome
Encephalopathy is a term that means brain disease, damage, or malfunction. In general, encephalopathy is manifested by an altered mental state.
Hypoplasia of the corpus callosum
MedGen UID:
138005
Concept ID:
C0344482
Congenital Abnormality
Underdevelopment of the corpus callosum.
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.
Bilateral tonic-clonic seizure
MedGen UID:
141670
Concept ID:
C0494475
Sign or Symptom
A bilateral tonic-clonic seizure is a seizure defined by a tonic (bilateral increased tone, lasting seconds to minutes) and then a clonic (bilateral sustained rhythmic jerking) phase.
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.
Diffuse cerebral atrophy
MedGen UID:
108958
Concept ID:
C0598275
Finding
Diffuse unlocalised atrophy affecting the cerebrum.
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.
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.
Upper limb spasticity
MedGen UID:
220882
Concept ID:
C1273957
Finding
Epileptic spasm
MedGen UID:
315948
Concept ID:
C1527366
Disease or Syndrome
A sudden flexion, extension, or mixed extension-flexion of predominantly proximal and truncal muscles that is usually more sustained than a myoclonic movement but not as sustained as a tonic seizure. Limited forms may occur
Generalized tonic seizure
MedGen UID:
322935
Concept ID:
C1836508
Disease or Syndrome
A generalized tonic seizure is a type of generalized motor seizure characterized by bilateral limb stiffening or elevation, often with neck stiffening without a subsequent clonic phase. The tonic activity can be a sustained abnormal posture, either in extension or flexion, sometimes accompanied by tremor of the extremities.
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
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Brisk reflexes
MedGen UID:
382164
Concept ID:
C2673700
Finding
Tendon reflexes that are noticeably more active than usual (conventionally denoted 3+ on clinical examination). Brisk reflexes may or may not indicate a neurological lesion. They are distinguished from hyperreflexia by the fact that hyerreflexia is characterized by hyperactive repeating (clonic) reflexes, which are considered to be always abnormal.
Ventriculomegaly
MedGen UID:
480553
Concept ID:
C3278923
Finding
An increase in size of the ventricular system of the brain.
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.
Atrophy/Degeneration affecting the brainstem
MedGen UID:
870454
Concept ID:
C4024900
Disease or Syndrome
CNS hypomyelination
MedGen UID:
892446
Concept ID:
C4025616
Finding
Reduced amount of myelin in the central nervous system resulting from defective myelinogenesis.
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.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.
Plagiocephaly
MedGen UID:
78562
Concept ID:
C0265529
Congenital Abnormality
Asymmetric head shape, which is usually a combination of unilateral occipital flattening with ipsilateral frontal prominence, leading to rhomboid cranial shape.
Secondary microcephaly
MedGen UID:
608952
Concept ID:
C0431352
Finding
Head circumference which falls below 2 standard deviations below the mean for age and gender because of insufficient head growth after birth.
Muscular atrophy
MedGen UID:
892680
Concept ID:
C0541794
Pathologic Function
The presence of skeletal muscular atrophy (which is also known as amyotrophy).
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Arthrogryposis multiplex congenita
MedGen UID:
1830310
Concept ID:
C5779613
Disease or Syndrome
Multiple congenital contractures in different body areas.
Respiratory insufficiency
MedGen UID:
11197
Concept ID:
C0035229
Pathologic Function
Impairment of gas exchange within the lungs secondary to a disease process, neoplasm, or trauma, possibly resulting in hypoxia, hypercarbia, or both, but not requiring intubation or mechanical ventilation. Patients are normally managed with pharmaceutical therapy, supplemental oxygen, or both.
Elevated circulating creatine kinase concentration
MedGen UID:
69128
Concept ID:
C0241005
Finding
An elevation of the level of the enzyme creatine kinase (also known as creatine phosphokinase (CK; EC 2.7.3.2) in the blood. CK levels can be elevated in a number of clinical disorders such as myocardial infarction, rhabdomyolysis, and muscular dystrophy.
Tongue fasciculations
MedGen UID:
65987
Concept ID:
C0239548
Finding
Fasciculations or fibrillation affecting the tongue muscle.
Upslanted palpebral fissure
MedGen UID:
98390
Concept ID:
C0423109
Finding
The palpebral fissure inclination is more than two standard deviations above the mean for age (objective); or, the inclination of the palpebral fissure is greater than typical for age.
Sparse eyebrow
MedGen UID:
371332
Concept ID:
C1832446
Finding
Decreased density/number of eyebrow hairs.
Narrow forehead
MedGen UID:
326956
Concept ID:
C1839758
Finding
Width of the forehead or distance between the frontotemporales is more than two standard deviations below the mean (objective); or apparently narrow intertemporal region (subjective).
Widely spaced teeth
MedGen UID:
337093
Concept ID:
C1844813
Finding
Increased spaces (diastemata) between most of the teeth in the same dental arch.
Low hanging columella
MedGen UID:
344656
Concept ID:
C1856119
Finding
Columella extending inferior to the level of the nasal base, when viewed from the side.
Synophrys
MedGen UID:
98132
Concept ID:
C0431447
Congenital Abnormality
Meeting of the medial eyebrows in the midline.
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.
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.
Deeply set eye
MedGen UID:
473112
Concept ID:
C0423224
Finding
An eye that is more deeply recessed into the plane of the face than is typical.
Absent smooth pursuit
MedGen UID:
870481
Concept ID:
C4024928
Finding
A complete lack of the ability to track objects with the ocular smooth pursuit system, a class of rather slow eye movements that minimizes retinal target motion.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVEarly-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome

Recent clinical studies

Etiology

Lehmann M, Ghosh PM, Madison C, Laforce R Jr, Corbetta-Rastelli C, Weiner MW, Greicius MD, Seeley WW, Gorno-Tempini ML, Rosen HJ, Miller BL, Jagust WJ, Rabinovici GD
Brain 2013 Mar;136(Pt 3):844-58. Epub 2013 Jan 28 doi: 10.1093/brain/aws327. PMID: 23358601Free PMC Article
Sobreira C, Marques W Jr, Pontes Neto OM, Santos AC, Pina Neto JM, Barreira AA
J Neurol Sci 2009 Mar 15;278(1-2):132-4. Epub 2009 Jan 14 doi: 10.1016/j.jns.2008.11.023. PMID: 19144360
Gauthier-Villars M, Landrieu P, Cormier-Daire V, Jacquemin E, Chrétien D, Rötig A, Rustin P, Munnich A, de Lonlay P
Neuropediatrics 2001 Jun;32(3):150-2. doi: 10.1055/s-2001-16614. PMID: 11521212
Gaggero R, Baglietto MP, Curia R, De Negri M
Childs Nerv Syst 1996 May;12(5):254-61. doi: 10.1007/BF00261806. PMID: 8737801
Schmitt HP, Härle M, Koelfen W, Nissen KH
Brain Dev 1994 Sep-Oct;16(5):386-92. doi: 10.1016/0387-7604(94)90126-0. PMID: 7892958

Diagnosis

Gilani A, Adang LA, Vanderver A, Collins A, Kleinschmidt-DeMasters BK
Pediatr Dev Pathol 2019 Nov-Dec;22(6):566-570. Epub 2019 Apr 5 doi: 10.1177/1093526619837797. PMID: 30952201Free PMC Article
Gauthier-Villars M, Landrieu P, Cormier-Daire V, Jacquemin E, Chrétien D, Rötig A, Rustin P, Munnich A, de Lonlay P
Neuropediatrics 2001 Jun;32(3):150-2. doi: 10.1055/s-2001-16614. PMID: 11521212
Felice KJ, Grunnet ML, Rao KR, Wolfson LI
Acta Neurol Scand 1997 Jan;95(1):60-4. doi: 10.1111/j.1600-0404.1997.tb00070.x. PMID: 9048988
Gaggero R, Baglietto MP, Curia R, De Negri M
Childs Nerv Syst 1996 May;12(5):254-61. doi: 10.1007/BF00261806. PMID: 8737801
Schmitt HP, Härle M, Koelfen W, Nissen KH
Brain Dev 1994 Sep-Oct;16(5):386-92. doi: 10.1016/0387-7604(94)90126-0. PMID: 7892958

Prognosis

Gilani A, Adang LA, Vanderver A, Collins A, Kleinschmidt-DeMasters BK
Pediatr Dev Pathol 2019 Nov-Dec;22(6):566-570. Epub 2019 Apr 5 doi: 10.1177/1093526619837797. PMID: 30952201Free PMC Article
Sobreira C, Marques W Jr, Pontes Neto OM, Santos AC, Pina Neto JM, Barreira AA
J Neurol Sci 2009 Mar 15;278(1-2):132-4. Epub 2009 Jan 14 doi: 10.1016/j.jns.2008.11.023. PMID: 19144360
Gauthier-Villars M, Landrieu P, Cormier-Daire V, Jacquemin E, Chrétien D, Rötig A, Rustin P, Munnich A, de Lonlay P
Neuropediatrics 2001 Jun;32(3):150-2. doi: 10.1055/s-2001-16614. PMID: 11521212
Gaggero R, Baglietto MP, Curia R, De Negri M
Childs Nerv Syst 1996 May;12(5):254-61. doi: 10.1007/BF00261806. PMID: 8737801
Schmitt HP, Härle M, Koelfen W, Nissen KH
Brain Dev 1994 Sep-Oct;16(5):386-92. doi: 10.1016/0387-7604(94)90126-0. PMID: 7892958

Clinical prediction guides

Sintini I, Kaufman K, Botha H, Martin PR, Loushin SR, Senjem ML, Reid RI, Schwarz CG, Jack CR Jr, Lowe VJ, Josephs KA, Whitwell JL, Ali F
Neuroimage Clin 2021;32:102850. Epub 2021 Oct 12 doi: 10.1016/j.nicl.2021.102850. PMID: 34655905Free PMC Article
Writzl K, Primec ZR, Stražišar BG, Osredkar D, Pečarič-Meglič N, Kranjc BS, Nishiyama K, Matsumoto N, Saitsu H
Epilepsia 2012 Jun;53(6):e106-10. Epub 2012 Mar 16 doi: 10.1111/j.1528-1167.2012.03437.x. PMID: 22429196
Gauthier-Villars M, Landrieu P, Cormier-Daire V, Jacquemin E, Chrétien D, Rötig A, Rustin P, Munnich A, de Lonlay P
Neuropediatrics 2001 Jun;32(3):150-2. doi: 10.1055/s-2001-16614. PMID: 11521212
Gaggero R, Baglietto MP, Curia R, De Negri M
Childs Nerv Syst 1996 May;12(5):254-61. doi: 10.1007/BF00261806. PMID: 8737801
Koo B, Becker LE, Chuang S, Merante F, Robinson BH, MacGregor D, Tein I, Ho VB, McGreal DA, Wherrett JR
Ann Neurol 1993 Jul;34(1):25-32. doi: 10.1002/ana.410340107. PMID: 8517676

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