PCH is an umbrella term that includes a group of heterogeneous, rare, and devastating neurodegenerative disorders. The new developments in genetic testing led to the description of new genes and phenotypes of PCH. So far, 13 types of PCH and 19 genes related to PCH are prescribed (1, 12, 13).
The updated classification highlights two significant aspects of the PCH. Although this disorder is degenerative, PCH8 and PCH11 are both non-degenerative ones (1, 14, 15, 16). Our results are partially in line with these studies because patient 4 (Female gender -PCH type 7) and patient 5 (Male gender-PCH type 11) could walk and speak few words compared to other patients. The studies showed all the types have prenatal onset except PCH2D, PCH2E, and PCH10, which have a postnatal onset. In our study, patient 1,2,4,5 had normal head circumference at birth. These results partly match the results of other studies. At the same time, Laugwitz et al. studied PCH type 11. He identified a homozygous frameshift variant in exon 9 of 18 of TBC1D23 predicting a loss of protein function. In this study, brain morphometry revealed a pattern of the pontine, brain stem, and supratentorial volume loss similar to PCH2 patients, although less pronounced. Intriguingly, cerebral MRI findings at the age of 1 and 15 years clearly showed progressive atrophy of the cerebellum, especially the hemispheres. In four of the cases reported in the literature, cerebellar hemispheres could be evaluated on the MRIs displayed, and they also showed atrophic foliage. While pontine hypoplasia and pronounced microcephaly are in line with previous reports on PCH11, the observations of this study clearly postnatal atrophy of the cerebellum argues for a different pathomechanism than in the other forms of PCH. It supports the hypothesis that TBC1D23 deficiency predominantly interferes with postnatal rather than with prenatal cerebellar development(17). In our study, PCH type 11- Patient 5 had only one MRI, so the comparison was not possible whether there was progressive atrophy of the cerebellum, but our patient could walk, speak, and attend school in spite that he was not doing well at school, so we think that the genetic defect determine the timing of cerebellar pathology in all types, but lots of studies should be performed in this field. The updated classification also highlights PCH type 2 is the most common form of this autosomal recessive disorder; despite this fact, non of our patients experienced this form (1,2).
Table.1 Detailed milestone, demographic, clinical, radiological, and genetic features of the patients
Pts/families
|
Patient 1/
Family 1
|
Patient2
Fmaily1
|
Patient3
Family2
|
Patient4
Family2
|
Patient5
Family3
|
PCH Type
|
10
|
10
|
7
|
7
|
11
|
Age(years)
|
5 (Ex age 5)
|
4.25
|
8.75
|
6.5
|
12
|
Age at diagnosis(years)
|
4.5
|
3.25
|
6.75
|
4.5
|
10.75
|
Age at application(years)
|
3.5
|
2.25
|
5.75
|
3.5
|
10.25
|
Consanguinity
|
Yes
|
Yes
|
Yes
|
Yes
|
Yes
|
HC(cm)
|
43
|
44
|
47
|
47
|
47
|
Gender
|
M
|
F
|
M
|
F
|
M
|
Birth Weight (Kg)
|
Term/2.100
|
Term/2.200
|
Term/2.700
|
Term/3.100
|
Term/3.200
|
Fetal Distress
|
No
|
No
|
No
|
No
|
No
|
Birth HC (cm)
|
33
|
33,5
|
32
|
33
|
33
|
Head Control
(Months)
|
7
|
4
|
8
|
5
|
5
|
Sitting Age (months)
|
No
Sitting
|
With hand support at 48
|
18
|
12
|
12
|
Walking Age (year)
|
No walking
|
No walking
|
No walking
|
At 3
Still walking
|
At 4
Still walking
|
Standford-Binnet Test
|
Severe delay
|
Severe delay
|
İntermediate delay
|
Minimal
delay
|
Minimal delay
|
Epilepsy
|
Yes
|
No
|
Yes
|
No
|
Yes
|
Anti-seizure medication
|
Levetiracetam
Vigabatrin
Topiramate
Phenobarbital
|
-
|
Valproic acid
Oxycarbamezepine
Phneobarbital
|
-
|
Levetiracetam
|
Neuropathy
|
Yes
|
No
|
No
|
No
|
No
|
Pyramidal/
Extrapyramidal
symptoms
|
Yes
|
Yes
|
Yes
|
Yes
|
Yes
|
Optic Atrophy
|
Yes
|
Yes
|
No
|
No
|
No
|
Scoliosis/
contractures
|
No
|
No
|
No
|
No
|
No
|
Abnormal
genitalia
|
No
|
No
|
Yes
|
No
|
No
|
Genetic
|
Clp1
c.419G > A(p.R140H)
Homozygous
mutation
|
Clp1
c.419G > A(p.R140H)
Homozygous
mutation
|
TOE 1
c.572A > G(p.N191S)
Homozygous
mutation
|
TOE
c.572A > G(p.N191S)
Homozygous
mutation
|
TBC1D23
c.524A > G
(p.Asn191Ser)
Homozygous
mutation
|
MRI-Ventral pons flattening
|
Yes
|
Yes /Min
|
No
|
No
|
Yes
|
MRI- Vermis hypoplasia
|
Yes
|
Yes/Min
|
Yes/Min
|
Yes/Min
|
Yes
|
MRI-Hypoplastic hemispheres
|
Yes
|
No
|
Yes
|
Yes
|
Yes/Min
|
Corpıs Callosum Hypoplasia
|
Minimal
|
No
|
Yes
|
Yes
|
No
|
MRI-Cortical atrophy
|
Yes
|
No
|
Yes
|
Yes
|
No
|
MRI-Abnormal myelination
|
Yes
|
No
|
No
|
No
|
No
|
MRI at Birth or specific age
|
Not available
|
Normal (at two years old)
|
Not available
|
Not available
|
Not available
|
In most cases, the disease is uniformly fatal early in life. Life span has ranged from death in the perinatal period to about 20–25 years of age. Only a few individuals-usually patients with PCH type 2-have survived to the second and third decades of life(1, 4). In our study PCH, type10 male gender died at the age of 5 due to recurrent respiratory infection and aspirations. In contrast, the rest of the patients are still at alive, experiencing some comorbidities. The mean age of the patients on our clinic application was 4.0 ± 2.45, and the diagnosis means age was 5.0 ± 2, which seems high. This could be due to the recently decreased cost of genetic testing and recently increased access to massively parallel or next-generation DNA sequencing.
Lots of Co-morbidities can associate PCH, sleep apnea, feeding problems, and epilepsy. Patients 1, 3, and 5 had seizures and used anti seizures medication. In our study, the expression of the PCH seemed to be milder in females than males. The female patient with PCH type 10 could sit with hand support, and she didn’t have any seizures, while the male patients with PCH type 10 couldn’t sit and were diagnosed with epilepsy and used anti seizures medication. The female with PCH type 7 didn’t have any anomaly in sex development and wasn’t diagnosed with epilepsy. In contrast, the male patients with PCH type7 had a disorder with sex development (absence of testis and micropenis was noticed) and he was diagnosed with epilepsy. Ethnicity also could play a significant role in the variation of expression in this disorder. So clinical manifestations could differ from a population to another. Thus lots of studies are needed (1, 2)
PCH does not always mean that there is a genetic background behind it. There are also non-genetic acquired reasons such as congenital cytomegalovirus infections, hemorrhage, ischemia, exposures to teratogenic drugs like phenytoin and valproic acid, and extreme prematurity (< 32 weeks). Other genetic diseases as congenital disorders of glycosylation (type1a), dandy walker syndrome, α-dystroglycan related dystrophies (Walker Warburg, muscle eye brain disease, Fukuyama congenital muscular dystrophies), lissencephaly with cerebellar hypoplasia, CASK gene defect, RELN &VLDLR mutations, X-linked hoyeraal-Hreidrasson syndrome, pediatric-onset of spinocerebellar ataxia could mimic PCH and have to be checked especially in unresolved cases (the ones that don't have a genetic diagnosis of PCH) (18–26). But it is not understandable why some genetics, such as the BRF1 gene, are not considered as one of the PCH genes. Further studies may include these genes, specially BRF1, to be added to the 19 PCH genes.
The shared clinical profiles of 169 PCH patients published by Namavar et. were severe microcephaly, seizures, pyramidal/extrapyramidal involvement, and poor psychomotor development. The common clinical profiles of our patients included microcephaly, poor cognition, psychdevelopmental delay, pyramidal and extrapyramidal movements in all patients, and epilepsy in some of them. All the children in our study group were born term, unlike Namavar et al. study. Where prematurity was seen in 24% of children with PCH. Our results were partially matched the Namavar et al. study (3) but totally matched wafik et al. results that presented two cases of PCH10 in the Turkish population. The main complaints of these two cases were a severe psychomotor delay, progressive microcephaly, and constipation (27). However, intrafamilial phenotypic variability was suggested due to the variability in their brain abnormalities and clinical features. At the same time, non of our patients had fetal distress after birth. Neuropathy was seen in almost all our PCH types 10, which was in line with other studies that showed that neuropathy was mainly seen in PCH 9 and 10, and seizures were seen in patients 1,3, and 5.
Ethnic background is essential in setting some subtypes of PCH since some form is seen in specific ethnicity. PCH10 has only been prescribed in children of Turkish origin, while PCH2E is of Moroccan Jewish origin. Our study is compatible with these results because 2 of our patients were diagnosed with PCH type 10. Each type/subtype of PCH has characteristic features such as disorders of sex development most apparent in 46 XY, which could only see in PCH7. Our study was compatible with these results because the male patients with PCH type 7 had a disorder in sex development while the female one didn’t have such a problem(1, 2).
Radiological imaging helps to specify types/subtypes of PCH in which the pontine, cerebellum, and supratentorial regions of the brain could be affected. Similar radiological findings were observed in patients with identical mutations, but a correlation with clinical severity was not reported. The eighth pattern was seen in patients with PCH type 9 and dragonfly in PCH type 2. In our study, The main feature of MRI is a different degree of cerebellar hypoplasia and pontine involvement; this was compatible with other studies’ results. Genetic testings as NGS is generally helping the whole time, but no causative genes could not be seen in 40% of PCH cases.(28–30).
There is no specific treatment for any PCH; supportive measures as gavage PEG feeding in case of feeding problems and sleep monitoring in sleep apnea are required. Antiepileptic drugs such as phenobarbital and topiramate are reported to be very effective in the treatment of seizures in PCH, especially in PCH2A (1, 2). Our study showed that phenobarbital is effective in the treatment of monotherapy and even in polytherapy. When phenobarbıtal was added to the treatment, the seizures were stopped.
Limitation of the study
PCH is a sporadic disorder; the inability to include all the types is considered a limitation. Informative coronal views are lacking; this seems to be the second limitation.