Clinical, Cognitive and Behavioural Assessment in Children with Cerebellar Disorder

Round 1

Reviewer 1 Report

The authors reviewed clinical and assessment of children with cerebellar disease and diagnostic approach.

The article was well organized and easy to follow.

I have a few minor comments below.

   -There are probably too many small paragraphs in some pages, for example, page 6/18, line 222-230 which could be better organized.

   -A summarized table is helpful for a reader to appreciate overall content and might be added. For example, 3. Developmental Cerebellar Cognitive-Affective syndrome and/or 4. Diagnostic approach.

Author Response

Dear Reviewer 1

Thanks for your comments.
As you suggest, we have unified the sentences on page 6 lines 222-230 into one paragraph.
I think summarizing the dates of the diagnostic approach is a very good idea, so I have added a table at the end of Chapter 4

Reviewer 2 Report

The Authors described cerebellar disorders which are characterized clinically by specific signs and symptoms, often associated with neurodevelopmental disorder. the study summarizes the clinical and neuropsychological evaluation in children with cerebellar disorder, highlighting the specific characteristics of the child age useful to define a diagnostic pathway. It formulated a keynote very well.

Major revision

I think that when the Author describes genetic disorder it is worth to write about some information about genetic abnormalities.

The Author wrote in abstract:

,,The ultimate goal of clinicians is to combine clinical data and instrumental findings to formulate a precise diagnostic hypothesis, and thus request a specific genetic test in order to confirm their findings, wherever possible" 

Minor revision

Line 219

Correct name is Cockayne syndrome

Line 220

What is CGH syndrome? Please explain abbraviation

Author Response

thanks for your comments.

major revision: I added at the end of chapter 4 a paragraph in which I describe the most common genetic conditions associated with cerebellar alterations and the diagnostic approach in this area.

minor revision

line 219: I corrected in the text the term Cockayne

line 220: the term CGH is incorrect, thank you for pointing it out. I have replaced it with the correct term which is CDG, or congenital disorder of glycosylation.

Reviewer 3 Report

The work represents a significant contribution in the field of cerebellar neurodegeneration and its diagnosis:

 

1) You argue a lot about the main reasons for susceptibility of the cerebellum during its prolonged development compared to other brain regions, where its vulnerability to abnormal neuroembryology, neurological and developmental insults, such as toxic lesions, vascular lesions, and genetic mutations is increased.

 

As you clarify with patients with Joubert syndrome, diagnostic studies should be interpreted with caution due to potential verification biases and difficulties in measuring IQ in the presence of visual, communication, and motor deficits. In this regard, it is necessary to name other types of known cerebellar alterations based on genetic mutations, where the patient's family history may be important to identify a potentially genetic disorder. For example,the spinocerebellar ataxias (SCAs) are a group of autosomal dominant disorders characterized by progressive ataxia due to degeneration of the cerebellum and its afferent and efferent pathways. SCAs, always together with the cerebellar degeneration (ataxia), may exhibit clinical deficits in brainstem or eye, especially retina (like SCA7) or optic nerve. Increasing loss of visual function complicates the use of clinical scales to track the progression of motor symptoms, hampering ability to develop accurate biomarkers of disease progression, and thus test the efficacy of potential treatments.

SCA comprise more than 40 autosomal dominant neurodegenerative disorders that present principally with progressive ataxia. Within the past few years, studies of pathogenic mechanisms in the SCAs have led to the development of promising therapeutic strategies, especially for SCAs caused by polyglutamine-coding cytosine–adenine–guanine (CAG) repeats. A CAG repeat expansion within the open reading frame of the respective genes associated with the SCAs 1, 2, 3, 6, 7 and 17 and dentatorubral-pallidoluysian atrophy (DRPLA) encodes an elongated polyglutamine (polyQ) tract in the protein product.

Before I named SCA7, SCA7, as you already know, is caused by a CAG/polyglutamine (polyQ) repeat expansion in the ataxin-7 gene. It was previously reported that directed expression of polyQ-ataxin-7 in Bergmann glia (BG) in transgenic mice leads to ataxia and non-cell-autonomous Purkinje cell (PC) degeneration. These findings indicate that SCA7 disease pathogenesis involves a convergence of alterations in a variety of different cell types to fully recapitulate the cerebellar degeneration.

In general, SCAs fall into two major categories on the basis of their genetic mutations: SCAs caused by microsatellite repeat expansions and SCAs caused by point mutations. When considering disease-causative mechanisms, SCAs resulting from repeat expansions can be further divided into those caused by polyglutamine (polyQ)-coding CAG repeat expansions and those caused by non-protein-coding repeats. The pathogenic mechanisms of SCAs are complex and differ substantially among these diverse classes of the mutation.

For this reason, the use of genetic diagnosis in cases with a family history of cerebellar ataxias due to polynucleotide expansion would be of vital importance before any imaging and / or neurological diagnosis.

References:

• Ashizawa, T., Öz, G., & Paulson, H. L. (2018). Spinocerebellar ataxias: prospects and challenges for therapy development. Nature reviews. Neurology, 14(10), 590–605. https://doi.org/10.1038/s41582-018-0051-6
• Park Jun Young, Joo Kwangsic, Woo Se Joon (2020). Ophthalmic Manifestations and Genetics of the Polyglutamine Autosomal Dominant Spinocerebellar Ataxias: A Review. Neurosci., 21 August 2020 | https://doi.org/10.3389/fnins.2020.00892
• Jacob A. Parker, Shabbir H. Merchant, Sanaz Attaripour-Isfahani, Hyun Joo Cho, Patrick McGurrin, Brian P. Brooks, Albert R. La Spada, Mark Hallett, Laryssa A. Huryn, Silvina G. Horovitz. In vivo assessment of neurodegeneration in Spinocerebellar Ataxia type 7. Preprint: medRxiv 2020.10.05.20207340; doi: https://doi.org/10.1101/2020.10.05.20207340
• Furrer SA, Mohanachandran MS, Waldherr SM, Chang C, Damian VA, Sopher BL, Garden GA, La Spada AR. Spinocerebellar ataxia type 7 cerebellar disease requires the coordinated action of mutant ataxin-7 in neurons and glia, and displays non-cell-autonomous bergmann glia degeneration. J Neurosci. 2011 Nov 9;31(45):16269-78. doi: 10.1523/JNEUROSCI.4000-11.2011. PMID: 22072678; PMCID: PMC3256125.
• Niu C, Prakash TP, Kim A, Quach JL, Huryn LA, Yang Y, Lopez E, Jazayeri A, Hung G, Sopher BL, Brooks BP, Swayze EE, Bennett CF, La Spada AR. Antisense oligonucleotides targeting mutant Ataxin-7 restore visual function in a mouse model of spinocerebellar ataxia type 7. Sci Transl Med. 2018 Oct 31;10(465):eaap8677. doi: 10.1126/scitranslmed.aap8677. PMID: 30381411; PMCID: PMC6411060.

 

2) Line 321: It does not explain that it is “GM”.

    Line 409: Does not explain what is “GA”.

 

3) Another question would be how to differentiate Huntington's disease (HD) with diagnoses and neuroimaging. HD is one of at least nine polyglutamine neurodegenerative diseases in which disease-causing proteins accumulate in ubiquitin-positive inclusions within neurons. Considering that HD involves marked early neurodegeneration in the striatum, whereas the cerebellum is relatively spared despite the ubiquitous expression of full-length mutant huntingtin, implying that inherent tissue-specific differences determine susceptibility to the HD CAG mutation. To understand this tissue specificity, Fossale et al. (2011) compared early mutant huntingtin-induced gene expression changes in striatum to those in cerebellum in young Hdh CAG knock-in mice, prior to onset of evident pathological alterations. Endogenous levels of full-length mutant huntingtin caused qualitatively similar, but quantitatively different gene expression changes in the two brain regions.

Reference:

•  Fossale E, Seong IS, Coser KR, Shioda T, Kohane IS, Wheeler VC, Gusella JF, MacDonald ME, Lee JM. Differential effects of the Huntington's disease CAG mutation in striatum and cerebellum are quantitative not qualitative. Hum Mol Genet. 2011 Nov 1;20(21):4258-67. doi: 10.1093/hmg/ddr355. Epub 2011 Aug 12. PMID: 21840924; PMCID: PMC3188996.

 

Author Response

Thank you for your helpful comments

1. Thank you for emphasizing the importance of degenerative conditions such as SCAs. I added at the end of chapter 4 a citation to these conditions at the end of chapter to look for in case of cerebellar atrophy, specifying as you rightly remember that often these conditions have onset in adulthood, but that pediatric onset is possible, especially because of the phenomenon of anticipation in familial forms.
2. Line 321: "GM" means Grey matter, we have corrected the text accordingly.

        Line 409: "GA" means Gestational age, we have corrected the text       accordingly

3. Thank you for pointing out the importance of Huntington's Corea. I chose not to include this condition in the article for two fundamental reasons. First, the condition typically involves the extrapyramidal system, although cerebellar involvement is possible. Moreover, the onset is usually in adulthood and pediatric cases are very rare and usually almost exclusively in familial forms in which the diagnosis is suggested by the picture of the parent already affected.

Round 2

Reviewer 2 Report

I have no comments for Author.