Table 3.

Genes and Disorders of Interest in the Differential Diagnosis of VLDLR Cerebellar Hypoplasia

Gene(s)DisorderBrain ImagingNeurologic Findings
AHI1
CPLANE1
CC2D2A
CEP290
(~34 genes) 1		Joubert syndrome & related disorders 2"Molar tooth sign" (hypoplasia of cerebellar vermis & assoc brain stem abnormalities resembling a tooth)
  • DD & severe cognitive impairment (in some individuals)
  • Episodic hyperpnea or apnea &/or atypical eye movements
  • Truncal ataxia
ALG1
ALG6
PMM2
(~42 genes) 3		 Congenital disorders of glycosylation Cerebellar atrophy
  • DD/ID
  • Hypotonia & ataxia
  • Strabismus
ATCAY Cayman-type cerebellar ataxia (OMIM 601238) 4CH
  • Cerebellar ataxia w/wide-based gait
  • Dysarthria
  • Intention tremor
  • DD/ID
ATM Ataxia-telangiectasia 5Cerebellar atrophy (may not be obvious in very young individuals)
  • Choreoathetosis
  • Oculomotor apraxia
  • Progressive cerebellar ataxia beginning at ages 1-4 yrs
ATP8A2 CAMRQ4 (OMIM 615268)Cerebellar atrophy
  • Congenital cerebellar ataxia
  • ID
CA8 CAMRQ3 (OMIM 613227)
  • Congenital cerebellar ataxia
  • ID
EXOSC3
RARS2
SEPSECS
TSEN2
TSEN34
TSEN54
VRK1 6		PCH types 1 & 2 (see EXOSC3-PCH & TSEN54-PCH)Cerebellar vermis hypoplasia & hypoplasia of the pons (more severe than small pons seen in VLDLR-CH)
RELN RELN lissencephaly w/CH 7 (OMIM 257320)Cerebellar signs of RELN-LCH that differ from VLDLR-CH:
More significant lissencephaly w/anterior>posterior gradient
A malformed hippocampus
Profound CH w/complete absence of detectable folia
  • Congenital cerebellar ataxia
  • Hypotonia
  • ID
  • Epilepsy
  • Strabismus
SACS ARSACS (autosomal recessive spastic ataxia of Charlevoix-Saguenay)Atrophy of superior vermis
  • Distal muscle wasting
  • Distal sensorimotor neuropathy (predominant in legs)
  • Dysarthria
  • Early-onset ataxia
  • Extensor plantar reflexes
  • Horizontal gaze-evoked nystagmus
  • Spasticity
SIL1 Marinesco-Sjögren syndrome 8Cerebellar atrophy
  • Cerebellar ataxia
  • Mild-to-severe cognitive impairment
  • Hypotonia & muscle weakness
TWNK Infantile-onset spinocerebellar ataxia 9 (OMIM 271245)Atrophy of cerebellum, brain stem, & spinal cord
  • Normal development until age 1 yr, followed by onset of ataxia, muscle hypotonia, loss of deep-tendon reflexes, athetosis, ophthalmoplegia, & sensorineural deafness in childhood 10
  • Epilepsy can → serious & often fatal encephalopathy.
WDR81 CAMRQ2 (OMIM 610185)CH
  • Congenital cerebellar ataxia
  • ID

CAMRQ = cerebellar ataxia, mental retardation, and dysequilibrium syndrome; CDG = congenital disorder of glycosylation; CH = cerebellar hypoplasia; DD = developmental delay; ID = intellectual disability; LCH = lissencephaly with cerebellar hypoplasia; PCH = pontocerebellar hypoplasia

1.

To date, pathogenic variants in 34 genes are known to cause Joubert syndrome. AHI1, CPLANE1, CC2D2A, and CEP290 are some of the most commonly involved genes.

2.

Variable features include: retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities.

3.

PMM2-CDG (CDG-Ia), ALG6-CDG (CDG-Ic), and ALG1-CDG (CDG-Ik) represent some of the more frequently identified CDG types. Forty-two different enzymes in the N-linked oligosaccharide synthetic pathway or interactive pathways are currently recognized to be deficient in each of the types of CDG-N-linked or among the multiple-pathway disorders (see Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview).

4.

Affected individuals are from a Grand Cayman Island isolate.

5.

Also characterized by immunodeficiency, frequent infections, telangiectasias of the conjunctivae, and increased risk for malignancy (particularly leukemia and lymphoma)

6.

About 50% of individuals with pontocerebellar hypoplasia type 1 (PCH1) have pathogenic variants in EXOSC3. See Pontocerebellar hypoplasia: OMIM Phenotypic Series for other genes associated with PCH in OMIM.

7.

The presentation of lissencephalies with cerebellar hypoplasia (LCH) ranges from the classic pattern of pachygyria/agyria to less severe phenotypes. The cerebellar manifestations range from relatively preserved hemispheres to marked hypoplasia with foliation defects. The malformations seen in VLDLR-CH fall within the LCH spectrum. Forms of LCH other than RELN-LCH are easily distinguished from VLDLR-CH based on the severity of the cortical phenotype or additional features.

8.

Also characterized by early-onset cataracts

9.

Infantile-onset spinocerebellar ataxia is well recognized in Finland.

10.

By adolescence affected individuals are profoundly deaf and no longer ambulatory; sensory axonal neuropathy, optic atrophy, autonomic nervous system dysfunction, and hypergonadotropic hypogonadism in females become evident.

From: VLDLR Cerebellar Hypoplasia

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